Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: SIRT2 localizes to the nucleus, particularly during G2/M transition and mitosis. North and Verdin (PMID:17726514) demonstrated that SIRT2 undergoes nucleo-cytoplasmic shuttling via CRM1-dependent nuclear export, with nuclear accumulation during mitosis. Reason: Well-supported by multiple experimental studies. SIRT2 shuttles between cytoplasm and nucleus, with nuclear enrichment during mitosis where it associates with chromatin and deacetylates H4K16. Supporting Evidence: PMID:17726514 SIRT2 maintains a largely cytoplasmic localization during interphase by active nuclear export in a Crm1-dependent manner... During the cell cycle, SIRT2 becomes enriched in the nucleus PMID:23908241 during infection with the bacterium Listeria monocytogenes, the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus file:human/SIRT2/SIRT2-deep-research-falcon.md See deep research file for comprehensive analysis
GO:0017136 histone deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: SIRT2 is a well-established NAD-dependent histone deacetylase. Crystal structure (PMID:11427894) reveals NAD-binding domain and catalytic mechanism. Deacetylates H4K16 preferentially (PMID:16648462), as well as H3K18 and H3K56. Reason: Core molecular function of SIRT2 confirmed by structural and biochemical studies. The NAD-dependent deacetylase activity is fundamental to all sirtuin functions. Supporting Evidence: PMID:11427894 Sir2 is an NAD-dependent histone deacetylase... The 1.7 A crystal structure of the 323 amino acid catalytic core of human SIRT2 PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
GO:0000183 rDNA heterochromatin formation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: This annotation is based on yeast Sir2 function. While SIRT2 has chromatin-related functions, direct evidence for human SIRT2 involvement in rDNA heterochromatin formation is limited. Reason: Inferred from yeast Sir2 function. Human SIRT2 is primarily cytoplasmic and its chromatin functions are more related to mitotic H4K16 deacetylation than rDNA silencing. The IBA annotation may be conservative but represents possible ancestral function.
GO:0000781 chromosome, telomeric region	IEA GO_REF:0000108	UNDECIDED	Summary: Automated annotation based on inter-ontology links. While yeast Sir2 functions in telomeric silencing, direct evidence for human SIRT2 at telomeres is limited. Reason: Lacks direct experimental evidence for human SIRT2. This may be extrapolated from yeast Sir2 telomeric functions. SIRT2 does associate with chromatin during mitosis but telomeric localization specifically is not well documented.
GO:0002376 immune system process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 has been implicated in immune responses, particularly through its role in NF-kB regulation (PMID:21081649) and bacterial infection response (PMID:23908241). Reason: While SIRT2 deacetylates p65/RELA and modulates NF-kB signaling, this represents a downstream consequence of its deacetylase activity rather than a core function. The term is also quite broad. Supporting Evidence: PMID:21081649 SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo at Lys310
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation. Nuclear localization is well-supported experimentally. Reason: Consistent with IBA annotation and experimental evidence showing SIRT2 nuclear shuttling and enrichment during mitosis.
GO:0005694 chromosome	IEA GO_REF:0000044	ACCEPT	Summary: SIRT2 associates with chromosomes during mitosis, where it deacetylates H4K16 to promote chromatin condensation. Reason: Supported by experimental evidence showing SIRT2 association with mitotic chromatin and its role in H4K16 deacetylation during cell cycle. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: SIRT2 is predominantly cytoplasmic during interphase, maintained by active CRM1-dependent nuclear export. Reason: Well-established primary localization of SIRT2. Multiple studies confirm cytoplasmic residence during interphase where it functions as tubulin deacetylase. Supporting Evidence: PMID:17726514 SIRT2 often appears distinctly localized in the cytoplasm... SIRT2 was exclusively cytoplasmic in 99.5% of cells
GO:0005813 centrosome	IEA GO_REF:0000044	ACCEPT	Summary: SIRT2 localizes to centrosomes during prophase, colocalizing with Aurora A kinase. Reason: Well-supported by immunofluorescence studies showing SIRT2 enrichment at centrosomes during early mitosis. Supporting Evidence: PMID:17726514 During early prophase, endogenous SIRT2 became enriched at the centrosome demonstrated by its colocalization with Aurora A
GO:0005814 centriole	IEA GO_REF:0000044	ACCEPT	Summary: SIRT2 localizes to centrioles during metaphase. Reason: Experimentally supported localization during mitosis. Supporting Evidence: PMID:17726514 At metaphase, SIRT2 remained concentrated in the centrioles and spread along the spindle fibers
GO:0005819 spindle	IEA GO_REF:0000044	ACCEPT	Summary: SIRT2 localizes along spindle fibers during metaphase. Reason: Well-documented localization pattern during mitosis, consistent with SIRT2's role in cell cycle regulation. Supporting Evidence: PMID:17726514 At metaphase, SIRT2 remained concentrated in the centrioles and spread along the spindle fibers
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: SIRT2 associates with microtubule cytoskeleton as tubulin deacetylase. Reason: Consistent with SIRT2's well-established role as alpha-tubulin K40 deacetylase.
GO:0005874 microtubule	IEA GO_REF:0000043	ACCEPT	Summary: SIRT2 associates with microtubules as the primary tubulin deacetylase. Reason: Core localization related to tubulin deacetylase function. SIRT2 deacetylates alpha-tubulin at K40.
GO:0006351 DNA-templated transcription	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 regulates transcription through histone deacetylation and deacetylation of transcription factors (FOXO, p65, HIF1A). Reason: This is an indirect/downstream effect of SIRT2's deacetylase activity on chromatin and transcription factors, not a direct transcriptional function.
GO:0006914 autophagy	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 regulates autophagy through deacetylation of FOXO1 (PMID:20543840). Acetylated FOXO1 binds ATG7 to induce autophagy. Reason: SIRT2 negatively regulates autophagy by deacetylating FOXO1. This is a documented but not core function. Supporting Evidence: PMID:20543840 In response to stress, FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2)... the acetylated FoxO1 bound to Atg7
GO:0007399 nervous system development	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 is involved in peripheral nerve myelination through Par-3/aPKC signaling (PMID:21949390). Reason: Documented role in Schwann cell myelination but this is a tissue-specific function rather than a core molecular function. Supporting Evidence: PMID:21949390 Sirt2 deacetylates Par-3, a master regulator of cell polarity
GO:0016740 transferase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: SIRT2 has been reported to possess ADP-ribosyltransferase activity (PMID:10381378). Reason: While sirtuins can exhibit weak ADP-ribosyltransferase activity, this is not considered a major physiological function of SIRT2. The term is also very general and uninformative.
GO:0017136 histone deacetylase activity, NAD-dependent	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation - core molecular function of SIRT2. Reason: Fundamental enzymatic activity confirmed by structural and biochemical studies.
GO:0030154 cell differentiation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 has been implicated in differentiation of various cell types including muscle (PMID:12887892), adipocytes, and oligodendrocytes. Reason: Very broad term. SIRT2 affects differentiation through its deacetylase activity on various substrates, but this is not a core molecular function.
GO:0030426 growth cone	IEA GO_REF:0000044	UNDECIDED	Summary: Localization based on UniProt subcellular location annotation. Reason: Limited direct experimental evidence for SIRT2 localization to growth cones. May be inferred from neuronal expression and microtubule association.
GO:0030496 midbody	IEA GO_REF:0000120	ACCEPT	Summary: SIRT2 localizes to the midbody during cytokinesis, colocalizing with Aurora B. Reason: Well-documented localization during cytokinesis. Supporting Evidence: PMID:17726514 during cytokinesis, SIRT2 associated with the midbody... SIRT2 colocalized with Aurora B, a midbody-localized protein
GO:0034979 NAD-dependent protein lysine deacetylase activity	IEA GO_REF:0000120	ACCEPT	Summary: Core molecular function - SIRT2 deacetylates numerous protein substrates including histones, tubulin, and transcription factors in an NAD-dependent manner. Reason: Fundamental enzymatic activity of SIRT2 supported by extensive biochemical evidence.
GO:0042995 cell projection	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: General localization potentially related to microtubule association in neuronal projections. Reason: Broad term that may be inferred from SIRT2's microtubule association and expression in neurons.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT2 promotes proteasomal degradation of substrates like HIF1A by deacetylating them, which increases their ubiquitination (PMID:24681946). Reason: Indirect effect - SIRT2 deacetylates substrates, which can then be ubiquitinated and degraded. This is a downstream consequence of deacetylase activity. Supporting Evidence: PMID:24681946 Deacetylation of HIF-1alpha by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2... and increased HIF-1alpha hydroxylation and ubiquitination
GO:0043204 perikaryon	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Neuronal cell body localization based on expression in neurons. Reason: Consistent with SIRT2 expression in neurons but represents tissue-specific rather than core localization.
GO:0043209 myelin sheath	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: SIRT2 is highly expressed in myelin and functions in peripheral myelination (PMID:21949390). Reason: Tissue-specific localization in Schwann cells related to myelination function. Supporting Evidence: PMID:21949390 Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination
GO:0043687 post-translational protein modification	IEA GO_REF:0000120	ACCEPT	Summary: SIRT2 performs deacetylation and defatty-acylation, both post-translational modifications. Reason: Accurate but very broad description of SIRT2's enzymatic function.
GO:0045087 innate immune response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 modulates innate immunity through NF-kB regulation and response to bacterial infection (PMID:23908241). Reason: Downstream effect of deacetylase activity on immune signaling pathways.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: SIRT2 contains a zinc-binding domain essential for structure and function. Reason: Should be more specific - SIRT2 binds zinc ion, not general metal ions. Proposed replacements: zinc ion binding Supporting Evidence: PMID:11427894 a smaller domain composed of a helical module and a zinc-binding module
GO:0046890 regulation of lipid biosynthetic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT2 regulates lipid biosynthesis by deacetylating and destabilizing ACLY (PMID:23932781). Reason: Documented role in lipid metabolism through ACLY regulation, but this is a downstream metabolic consequence of deacetylase activity. Supporting Evidence: PMID:23932781 the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IEA GO_REF:0000117	ACCEPT	Summary: SIRT2 preferentially deacetylates H4K16, particularly during mitosis, promoting chromatin condensation (PMID:16648462). Reason: Well-established specific substrate preference of SIRT2. H4K16 is the preferred histone substrate. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16
GO:0051093 negative regulation of developmental process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Very broad term - SIRT2 affects various developmental processes including muscle differentiation and adipogenesis. Reason: Too broad and vague. More specific terms should be used for SIRT2's roles in specific developmental contexts.
GO:0051239 regulation of multicellular organismal process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Extremely broad term reflecting SIRT2's pleiotropic effects. Reason: Too general to be informative. More specific process terms are appropriate.
GO:0051287 NAD binding	IEA GO_REF:0000002	ACCEPT	Summary: SIRT2 requires NAD+ as a cofactor for its deacetylase/defatty-acylase activity. Reason: Confirmed by crystal structure showing NAD-binding Rossmann fold domain. Supporting Evidence: PMID:11427894 reveals an NAD-binding domain, which is a variant of the Rossmann fold
GO:0051301 cell division	IEA GO_REF:0000043	ACCEPT	Summary: SIRT2 regulates cell division through multiple mechanisms including chromatin condensation, spindle checkpoint, and cytokinesis. Reason: Core biological process for SIRT2. Well-supported by localization studies and functional analyses. Supporting Evidence: PMID:17726514 SIRT2 contributes to the proper progression through mitosis PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit
GO:0051321 meiotic cell cycle	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT2 has been implicated in oocyte maturation and meiosis regulation. Reason: Evidence for meiotic roles exists but is less extensive than mitotic functions.
GO:0062013 positive regulation of small molecule metabolic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Broad term reflecting SIRT2's metabolic regulatory functions. Reason: Too general. More specific metabolic process terms are more informative.
GO:0070403 NAD+ binding	IEA GO_REF:0000002	ACCEPT	Summary: SIRT2 binds NAD+ as essential cofactor for catalysis. Reason: Core requirement for SIRT2 enzymatic activity confirmed structurally. Supporting Evidence: PMID:11427894 Sir2 is an NAD-dependent histone deacetylase
GO:0071456 cellular response to hypoxia	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT2 regulates hypoxia response by deacetylating HIF1A, promoting its hydroxylation and degradation (PMID:24681946). Reason: Well-documented role through HIF1A regulation but represents downstream effect of deacetylase activity. Supporting Evidence: PMID:24681946 SIRT2-mediated deacetylation of HIF-1alpha regulates its stability in tumour cells
GO:0140773 NAD-dependent protein demyristoylase activity	IEA GO_REF:0000116	ACCEPT	Summary: SIRT2 possesses efficient demyristoylase activity with kcat/Km higher than deacetylase activity (PMID:25704306). Reason: Well-characterized enzymatic activity supported by kinetic and structural studies. Supporting Evidence: PMID:25704306 The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group
GO:0140774 NAD-dependent protein depalmitoylase activity	IEA GO_REF:0000116	ACCEPT	Summary: SIRT2 can remove palmitoyl groups from lysine residues, though less efficiently than myristoyl groups. Reason: Documented defatty-acylase activity, though myristoyl substrates are preferred. Supporting Evidence: PMID:25704306 the defatty-acylase activity toward palmitoyl groups is not efficient, which may result from the limited depth of the active site
GO:0005515 protein binding	IPI PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	MODIFY	Summary: General protein binding based on interaction with CDC14B and other cell cycle regulators. Reason: Protein binding is uninformative. The referenced paper shows SIRT2 interacts with CDC14B phosphatase in context of mitotic regulation. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0005515 protein binding	IPI PMID:12887892 Sir2 regulates skeletal muscle differentiation	MODIFY	Summary: Interaction with MyoD transcription factor in context of muscle differentiation. Reason: Should be more specific - SIRT2 binds transcription factors to regulate their activity. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	REMOVE	Summary: Large-scale protein interaction mapping study. Reason: Generic protein binding annotation from high-throughput screen is uninformative. More specific interaction terms should be used. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry.
GO:0005515 protein binding	IPI PMID:21081649 SIRT2 regulates NF-κB dependent gene expression through deac...	MODIFY	Summary: Interaction with p65/RELA subunit of NF-kB. Reason: Should be annotated with more specific term for transcription factor binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:21081649 SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	REMOVE	Summary: Protein interactome study for autism-related pathways. Reason: Generic protein binding from interaction screen is uninformative. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders.
GO:0005515 protein binding	IPI PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N...	KEEP AS NON CORE	Summary: Interaction with G6PD (glucose-6-phosphate dehydrogenase). Reason: Represents a specific substrate interaction. SIRT2 deacetylates G6PD to regulate pentose phosphate pathway. Supporting Evidence: PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.
GO:0005515 protein binding	IPI PMID:24825348 SIRT2 induces the checkpoint kinase BubR1 to increase lifesp...	MODIFY	Summary: Interaction with BubR1 checkpoint kinase. Reason: Should use more specific term. SIRT2 deacetylates BubR1 in spindle checkpoint. Proposed replacements: protein kinase binding Supporting Evidence: PMID:24825348 SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: High-throughput proteome-scale interaction study. Reason: Generic protein binding from large-scale screen is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox ...	MODIFY	Summary: Interaction with HOXA10 homeobox transcription factor. Reason: Should be more specific - transcription factor binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10.
GO:0005515 protein binding	IPI PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	MODIFY	Summary: Interaction with FOXO1 transcription factor. Reason: SIRT2 binds and deacetylates FOXO1. Should be transcription factor binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:20543840 FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2)
GO:0005515 protein binding	IPI PMID:27512957 Oncogenic microtubule hyperacetylation through BEX4-mediated...	KEEP AS NON CORE	Summary: Interaction with BEX4 which inhibits SIRT2 tubulin deacetylase activity. Reason: Documents regulatory interaction but protein binding term is too general. Supporting Evidence: PMID:27512957 Oncogenic microtubule hyperacetylation through BEX4-mediated sirtuin 2 inhibition.
GO:0005515 protein binding	IPI PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	MODIFY	Summary: Interaction with HIF1A. Reason: SIRT2 binds and deacetylates HIF1A transcription factor. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:24681946 SIRT2 directly interacted with HIF-1alpha and deacetylated Lys709 of HIF-1alpha
GO:0005515 protein binding	IPI PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase acti...	MODIFY	Summary: Interaction with p300 acetyltransferase. Reason: SIRT2 is acetylated and regulated by p300. Should use histone acetyltransferase binding. Proposed replacements: histone acetyltransferase binding Supporting Evidence: PMID:18722353 p300 interacts with Sirt2... and triggers the acetylation
GO:0005515 protein binding	IPI PMID:21949390 Sir-two-homolog 2 (Sirt2) modulates peripheral myelination t...	KEEP AS NON CORE	Summary: Interaction with Par-3 polarity protein. Reason: Specific substrate interaction in context of myelination. Supporting Evidence: PMID:21949390 Sirt2 deacetylates Par-3, a master regulator of cell polarity
GO:0005515 protein binding	IPI PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	KEEP AS NON CORE	Summary: Interaction with ACLY (ATP-citrate lyase). Reason: Specific substrate interaction. SIRT2 deacetylates ACLY to regulate lipid metabolism. Supporting Evidence: PMID:23932781 the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY
GO:0005515 protein binding	IPI PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	MODIFY	Summary: Interaction with Aurora A and Aurora B kinases. Reason: SIRT2 interacts with Aurora kinases during mitosis. Should be protein kinase binding. Proposed replacements: protein kinase binding Supporting Evidence: PMID:17726514 coimmunoprecipitation experiments with FLAG-tagged SIRT2 and Myc-tagged Aurora A indicate that these two proteins interact
GO:0005515 protein binding	IPI PMID:17172643 Multiple histone deacetylases and the CREB-binding protein r...	MODIFY	Summary: Interaction with CBP in context of pre-mRNA 3-end processing. Reason: CBP is a histone acetyltransferase. Should use more specific term. Proposed replacements: histone acetyltransferase binding Supporting Evidence: PMID:17172643 2006 Dec 17. Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 represses transcription through histone deacetylation and transcription factor modification. Reason: Indirect effect through substrate modification.
GO:0004407 histone deacetylase activity	IEA GO_REF:0000107	MODIFY	Summary: General HDAC activity - should be NAD-dependent specific term. Reason: SIRT2 is a class III NAD-dependent HDAC, not a Zn-dependent HDAC. Proposed replacements: histone deacetylase activity, NAD-dependent
GO:0005739 mitochondrion	IEA GO_REF:0000107	REMOVE	Summary: SIRT2 is primarily cytoplasmic, not mitochondrial. Reason: SIRT2 is the cytoplasmic sirtuin. SIRT3-5 are the mitochondrial sirtuins. Any mitochondrial detection likely represents contamination.
GO:0016042 lipid catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 affects lipid metabolism through multiple substrates. Reason: Metabolic consequence of deacetylase activity.
GO:0022011 myelination in peripheral nervous system	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 regulates peripheral myelination. Reason: Tissue-specific function documented in mouse studies.
GO:0031641 regulation of myelination	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 regulates myelination through Par-3/aPKC pathway. Reason: Tissue-specific function.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: SIRT2 promotes substrate degradation through deacetylation. Reason: Indirect effect.
GO:0033010 paranodal junction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 localization in myelin structures. Reason: Tissue-specific localization.
GO:0033558 protein lysine deacetylase activity	IEA GO_REF:0000107	ACCEPT	Summary: Broad deacetylase activity on non-histone substrates. Reason: Core enzymatic function - SIRT2 deacetylates many protein substrates.
GO:0034599 cellular response to oxidative stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 involved in oxidative stress response. Reason: Pleiotropic effect through various substrates.
GO:0040029 epigenetic regulation of gene expression	IEA GO_REF:0000107	ACCEPT	Summary: SIRT2 affects gene expression through histone deacetylation. Reason: Direct epigenetic function through H4K16 and H3K18 deacetylation.
GO:0042903 tubulin deacetylase activity	IEA GO_REF:0000120	ACCEPT	Summary: SIRT2 is the primary tubulin deacetylase. Reason: Core enzymatic function.
GO:0043220 Schmidt-Lanterman incisure	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 localization in myelin structures. Reason: Tissue-specific localization.
GO:0045599 negative regulation of fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 inhibits adipogenesis. Reason: Tissue-specific developmental function.
GO:0045836 positive regulation of meiotic nuclear division	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 role in meiosis from ortholog data. Reason: Less characterized than mitotic functions.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Context-dependent positive transcriptional regulation. Reason: Indirect effect - SIRT2 effects on transcription are substrate-dependent.
GO:0051781 positive regulation of cell division	IEA GO_REF:0000107	ACCEPT	Summary: SIRT2 promotes proper cell division. Reason: Consistent with cell cycle functions.
GO:0051987 positive regulation of attachment of spindle microtubules to kinetochore	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 role in spindle checkpoint. Reason: Related to cell cycle function.
GO:0061433 cellular response to caloric restriction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Sirtuins involved in metabolic adaptation. Reason: General sirtuin function.
GO:0071872 cellular response to epinephrine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 involved in hormonal metabolic responses. Reason: Physiological context.
GO:1900119 positive regulation of execution phase of apoptosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 can promote apoptosis in certain contexts. Reason: Context-dependent effect.
GO:1900195 positive regulation of oocyte maturation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 role in oocyte maturation. Reason: Tissue-specific function.
GO:2000378 negative regulation of reactive oxygen species metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT2 affects ROS through multiple pathways. Reason: Indirect effect.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nuclear localization confirmed by immunofluorescence in HPA/Cell Atlas. Reason: Consistent with SIRT2 nuclear shuttling and chromatin association.
GO:0005730 nucleolus	IDA GO_REF:0000052	REMOVE	Summary: Interestingly, SIRT2 appears to be excluded from nucleoli when nuclear. Reason: Contradicts published data showing SIRT2 is excluded from nucleoli. Supporting Evidence: PMID:17726514 Upon LMB treatment, SIRT2-FLAG was sequestered in the nucleus but was excluded from the nucleoli
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization confirmed by immunofluorescence. Reason: Primary localization of SIRT2 during interphase.
GO:0007084 mitotic nuclear membrane reassembly	TAS Reactome:R-HSA-2995410	KEEP AS NON CORE	Summary: SIRT2 involved in nuclear envelope reassembly pathway via ANKLE2 deacetylation. Reason: Documented Reactome pathway but represents specific mitotic function.
GO:0034979 NAD-dependent protein lysine deacetylase activity	TAS Reactome:R-HSA-9667952	ACCEPT	Summary: SIRT2 deacetylates ANKLE2 in Reactome pathway. Reason: Core enzymatic function in curated pathway.
GO:0140219 histone methacryllysine demethacrylase activity	IDA PMID:34961760 Histone lysine methacrylation is a dynamic post-translationa...	ACCEPT	Summary: SIRT2 can remove methacryl modification from histone lysines. Reason: Newly characterized enzymatic activity extending SIRT2's substrate range. Supporting Evidence: PMID:34961760 Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.
GO:0140228 histone benzoyllysine debenzoylase activity	IDA PMID:30154464 Lysine benzoylation is a histone mark regulated by SIRT2.	ACCEPT	Summary: SIRT2 regulates histone lysine benzoylation by removing benzoyl groups. Reason: Experimentally validated enzymatic activity. Supporting Evidence: PMID:30154464 Lysine benzoylation is a histone mark regulated by SIRT2.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	REMOVE	Summary: Mitochondrial localization from high-throughput proteomics. Reason: SIRT2 is primarily cytoplasmic. Mitochondrial detection likely reflects cytoplasmic contamination or non-specific association. SIRT3-5 are the established mitochondrial sirtuins. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	ACCEPT	Summary: Direct demonstration of NAD-dependent deacetylase activity on ACLY substrate. Reason: Core enzymatic function confirmed with specific substrate. Supporting Evidence: PMID:23932781 the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY
GO:1902725 negative regulation of satellite cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Inferred from mouse Sirt2 function in muscle. Reason: Supported by mouse studies but represents tissue-specific function.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	KEEP AS NON CORE	Summary: SIRT2 promotes HIF1A degradation by deacetylation leading to ubiquitination. Reason: Downstream effect of SIRT2 deacetylase activity on specific substrates. Supporting Evidence: PMID:24681946 Deacetylation of HIF-1alpha by SIRT2 resulted in... increased HIF-1alpha hydroxylation and ubiquitination
GO:0040029 epigenetic regulation of gene expression	IMP PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in ba...	ACCEPT	Summary: SIRT2 H3K18 deacetylation affects gene expression during infection. Reason: Direct epigenetic function through histone modification. Supporting Evidence: PMID:23908241 SIRT2 associates with the transcription start site of a subset of genes repressed during infection and deacetylates histone H3 on lysine 18
GO:1990404 NAD+-protein mono-ADP-ribosyltransferase activity	TAS NOT PMID:17456799 Sirtuin functions in health and disease.	ACCEPT	Summary: This is a NOT annotation indicating SIRT2 does not have NAD+-protein mono-ADP-ribosyltransferase activity per the cited review. Reason: The GOA record uses a NOT qualifier for this activity; we accept the negated annotation as the current curation position for SIRT2. Supporting Evidence: PMID:17456799 Apr 24. Sirtuin functions in health and disease.
GO:0045723 positive regulation of fatty acid biosynthetic process	IDA PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	REMOVE	Summary: Counter-intuitive annotation - SIRT2 actually destabilizes ACLY and should inhibit fatty acid synthesis. This annotation appears to be an error. Reason: SIRT2 deacetylates and destabilizes ACLY, which should NEGATIVELY regulate fatty acid synthesis, not positively. The referenced paper states SIRT2 deacetylates and destabilizes ACLY - stabilization of ACLY promotes lipid synthesis. Supporting Evidence: PMID:23932781 the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY
GO:0140773 NAD-dependent protein demyristoylase activity	IDA PMID:25704306 Efficient demyristoylase activity of SIRT2	ACCEPT	Summary: Kinetic and structural characterization of SIRT2 demyristoylase activity. Reason: Core enzymatic function with higher catalytic efficiency than deacetylation. Supporting Evidence: PMID:25704306 The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group
GO:0140773 NAD-dependent protein demyristoylase activity	IDA PMID:32103017 NMT1 and NMT2 are lysine myristoyltransferases regulating th...	ACCEPT	Summary: Demyristoylase activity demonstrated in cellular context. Reason: Additional experimental support for demyristoylase activity. Supporting Evidence: PMID:32103017 NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.
GO:0140774 NAD-dependent protein depalmitoylase activity	IDA PMID:32103017 NMT1 and NMT2 are lysine myristoyltransferases regulating th...	ACCEPT	Summary: Depalmitoylase activity demonstrated experimentally. Reason: Documented enzymatic activity though less efficient than demyristoylation. Supporting Evidence: PMID:32103017 NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:12887892 Sir2 regulates skeletal muscle differentiation	ACCEPT	Summary: SIRT2 interacts with MyoD transcription factor. Reason: More specific than generic protein binding. Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:15126506 FOXO4 is acetylated upon peroxide stress and deacetylated by...	REMOVE	Summary: Referenced paper is about SIRT1/FOXO4 interaction, not SIRT2. Reason: Incorrect gene - this paper describes SIRT1, not SIRT2, interacting with FOXO4. Supporting Evidence: PMID:15126506 2004 May 4. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).
GO:0003950 NAD+ poly-ADP-ribosyltransferase activity	IDA PMID:10381378 Characterization of five human cDNAs with homology to the ye...	REMOVE	Summary: Early study suggesting ADP-ribosyltransferase activity based on NAD labeling. Reason: The activity described was mono-ADP-ribosylation, not poly-ADP-ribosylation. SIRT2 does not have poly-ADP-ribosyltransferase activity. Annotation should be to GO:1990404 (NAD+-protein mono-ADP-ribosyltransferase activity) instead. Proposed replacements: NAD+-protein mono-ADP-ribosyltransferase activity Supporting Evidence: PMID:10381378 Recombinant E. coli cobB and human SIRT2 sirtuin proteins were able to cause radioactivity to be transferred from [32P]NAD to bovine serum albumin
GO:0005829 cytosol	TAS Reactome:R-HSA-9667952	ACCEPT	Summary: Cytosolic SIRT2 in Reactome pathway. Reason: Consistent with primary localization.
GO:0042903 tubulin deacetylase activity	IDA PMID:23886946 Furry promotes acetylation of microtubules in the mitotic sp...	ACCEPT	Summary: SIRT2 tubulin deacetylase activity demonstrated in mitotic spindle context. Reason: Well-established core function of SIRT2 on alpha-tubulin K40. Supporting Evidence: PMID:23886946 Jul 25. Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	KEEP AS NON CORE	Summary: SIRT2 negatively regulates HIF1A-dependent transcription by destabilizing HIF1A. Reason: Indirect transcriptional effect through substrate modification. Supporting Evidence: PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
GO:0005829 cytosol	IDA PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	ACCEPT	Summary: Cytosolic SIRT2 deacetylates HIF1A. Reason: Confirms cytosolic function. Supporting Evidence: PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Conserved function from ortholog data. Reason: Downstream effect of deacetylase activity.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IMP PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	ACCEPT	Summary: NAD-dependent deacetylation of HIF1A demonstrated by mutant analysis. Reason: Core function confirmed. Supporting Evidence: PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
GO:0071456 cellular response to hypoxia	IDA PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α ...	KEEP AS NON CORE	Summary: SIRT2 modulates hypoxia response through HIF1A regulation. Reason: Specific physiological context for SIRT2 function. Supporting Evidence: PMID:24681946 SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
GO:0005737 cytoplasm	IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	ACCEPT	Summary: Cytoplasmic localization where SIRT2 deacetylates FOXO1. Reason: Confirms cytoplasmic function. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.
GO:0006476 protein deacetylation	IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	ACCEPT	Summary: SIRT2 deacetylates FOXO1 transcription factor. Reason: Core biological process for SIRT2. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.
GO:0010507 negative regulation of autophagy	IMP PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	KEEP AS NON CORE	Summary: SIRT2 inhibits autophagy by deacetylating FOXO1. Reason: Documented but not core function. Supporting Evidence: PMID:20543840 FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2)... the acetylated FoxO1 bound to Atg7... to influence the autophagic process
GO:0033558 protein lysine deacetylase activity	IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	ACCEPT	Summary: SIRT2 deacetylates FOXO1. Reason: Confirms broad substrate specificity beyond histones. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.
GO:0034599 cellular response to oxidative stress	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 involved in oxidative stress response through multiple substrates. Reason: Pleiotropic effect through various substrates including FOXO factors.
GO:0042177 negative regulation of protein catabolic process	IMP PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ...	KEEP AS NON CORE	Summary: SIRT2 inhibits autophagy-mediated protein degradation. Reason: Indirect effect through autophagy regulation. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.
GO:0043388 positive regulation of DNA binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Inferred from ortholog - SIRT2 affects transcription factor DNA binding. Reason: Indirect effect through deacetylation of transcription factors.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Context-dependent transcriptional regulation. Reason: Indirect effect - SIRT2 can both activate and repress transcription depending on substrate.
GO:0061433 cellular response to caloric restriction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sirtuins involved in metabolic adaptation to caloric restriction. Reason: General sirtuin function but not uniquely characteristic of SIRT2.
GO:1900119 positive regulation of execution phase of apoptosis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 can promote apoptosis in certain contexts. Reason: Context-dependent effect, not core function.
GO:2000378 negative regulation of reactive oxygen species metabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 affects ROS through multiple pathways including FOXO factors. Reason: Indirect effect through substrate modification.
GO:0045836 positive regulation of meiotic nuclear division	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 role in meiosis inferred from orthologs. Reason: Less well-characterized than mitotic functions.
GO:0051781 positive regulation of cell division	ISS GO_REF:0000024	ACCEPT	Summary: SIRT2 promotes proper cell division. Reason: Consistent with well-documented mitotic functions.
GO:0051987 positive regulation of attachment of spindle microtubules to kinetochore	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 role in spindle checkpoint. Reason: Related to cell cycle function but specific mechanism unclear.
GO:1900195 positive regulation of oocyte maturation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 role in oocyte maturation from ortholog data. Reason: Tissue-specific developmental function.
GO:0006476 protein deacetylation	IDA PMID:21949390 Sir-two-homolog 2 (Sirt2) modulates peripheral myelination t...	ACCEPT	Summary: SIRT2 deacetylates Par-3 in Schwann cells. Reason: Core biological process demonstrated with specific substrate. Supporting Evidence: PMID:21949390 Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.
GO:0010801 negative regulation of peptidyl-threonine phosphorylation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 affects phosphorylation through aPKC regulation in myelination. Reason: Specific to Schwann cell function.
GO:0022011 myelination in peripheral nervous system	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 regulates peripheral myelination through Par-3/aPKC. Reason: Tissue-specific function well-documented in mouse. Supporting Evidence: PMID:21949390 Sirt2 deacetylates Par-3, a master regulator of cell polarity
GO:0031641 regulation of myelination	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 regulates Schwann cell myelination. Reason: Tissue-specific function.
GO:0033010 paranodal junction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 localization in myelin structures from mouse studies. Reason: Tissue-specific localization in myelinating cells.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:21949390 Sir-two-homolog 2 (Sirt2) modulates peripheral myelination t...	ACCEPT	Summary: NAD-dependent deacetylation of Par-3. Reason: Core enzymatic function. Supporting Evidence: PMID:21949390 Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.
GO:0043219 lateral loop	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 localization in myelin structures. Reason: Tissue-specific localization.
GO:0043220 Schmidt-Lanterman incisure	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 localization in myelin structures. Reason: Tissue-specific localization.
GO:0003682 chromatin binding	IDA PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in ba...	ACCEPT	Summary: SIRT2 associates with transcription start sites during bacterial infection. Reason: Demonstrated by ChIP showing SIRT2 at gene promoters. Supporting Evidence: PMID:23908241 SIRT2 associates with the transcription start site of a subset of genes repressed during infection
GO:0005634 nucleus	IDA PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in ba...	ACCEPT	Summary: SIRT2 translocates to nucleus during bacterial infection. Reason: Demonstrates stimulus-induced nuclear translocation. Supporting Evidence: PMID:23908241 the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus
GO:0005737 cytoplasm	IDA PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in ba...	ACCEPT	Summary: SIRT2 is cytoplasmic under basal conditions. Reason: Primary localization confirmed. Supporting Evidence: PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection.
GO:0016042 lipid catabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 affects lipid metabolism through ACLY and other substrates. Reason: Metabolic consequence of deacetylase activity.
GO:0033558 protein lysine deacetylase activity	IMP PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in ba...	ACCEPT	Summary: SIRT2 deacetylase activity required for H3K18 deacetylation during infection. Reason: Confirms deacetylase function in physiological context. Supporting Evidence: PMID:23908241 A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection.
GO:0071872 cellular response to epinephrine stimulus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 involved in metabolic responses to hormonal stimuli. Reason: Physiological context for metabolic regulation.
GO:0045599 negative regulation of fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 inhibits adipocyte differentiation. Reason: Tissue-specific developmental function.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase acti...	KEEP AS NON CORE	Summary: SIRT2 inhibits p53-dependent transcription when active. Reason: Indirect transcriptional effect. Supporting Evidence: PMID:18722353 the acetylation of Sirt2 by p300 relieves the inhibitory effect of Sirt2 on the transcriptional activity of p53
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase acti...	ACCEPT	Summary: SIRT2 NAD-dependent deacetylase activity regulated by p300 acetylation. Reason: Core function with regulatory mechanism characterized. Supporting Evidence: PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase activity.
GO:0042903 tubulin deacetylase activity	IDA PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase acti...	ACCEPT	Summary: SIRT2 deacetylates tubulin. Reason: Duplicate of well-supported core function. Supporting Evidence: PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase activity.
GO:0090042 tubulin deacetylation	IDA PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase acti...	ACCEPT	Summary: SIRT2 deacetylates tubulin. Reason: Core biological process for cytoplasmic SIRT2. Supporting Evidence: PMID:18722353 Acetylation of Sirt2 by p300 attenuates its deacetylase activity.
GO:0000792 heterochromatin	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 associates with heterochromatin, inferred from Sir2 function. Reason: Chromatin association during mitosis is documented, but constitutive heterochromatin localization is less clear.
GO:0005634 nucleus	IDA PMID:16648462 SirT2 is a histone deacetylase with preference for histone H...	ACCEPT	Summary: SIRT2 enters nucleus during mitosis for H4K16 deacetylation. Reason: Cell cycle-dependent nuclear localization. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis.
GO:0005694 chromosome	IDA PMID:16648462 SirT2 is a histone deacetylase with preference for histone H...	ACCEPT	Summary: SIRT2 associates with chromosomes during mitosis. Reason: Consistent with H4K16 deacetylation function during mitosis. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis.
GO:0005737 cytoplasm	IDA PMID:16648462 SirT2 is a histone deacetylase with preference for histone H...	ACCEPT	Summary: Primary cytoplasmic localization during interphase. Reason: Well-established localization pattern. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis.
GO:0033270 paranode region of axon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 in myelin structures from mouse data. Reason: Tissue-specific localization.
GO:0043204 perikaryon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Neuronal cell body localization. Reason: Tissue-specific localization.
GO:0043209 myelin sheath	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 in myelin from mouse studies. Reason: Tissue-specific localization.
GO:0044224 juxtaparanode region of axon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 in axonal structures from mouse data. Reason: Tissue-specific localization.
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IDA PMID:16648462 SirT2 is a histone deacetylase with preference for histone H...	ACCEPT	Summary: SIRT2 shows preference for H4K16 deacetylation during mitosis. Reason: Specific substrate preference established by biochemical studies. Supporting Evidence: PMID:16648462 SirT2 is a histone deacetylase with preference for histone H4 Lys 16
GO:0070446 negative regulation of oligodendrocyte progenitor proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT2 role in CNS myelination from mouse studies. Reason: Tissue-specific function.
GO:0090042 tubulin deacetylation	ISS GO_REF:0000024	ACCEPT	Summary: Conserved tubulin deacetylation function. Reason: Core biological process for SIRT2.
GO:0004407 histone deacetylase activity	IDA PMID:17488717 Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dep...	MODIFY	Summary: SIRT2 histone deacetylase activity regulated by CDK1 phosphorylation. Reason: Should be the more specific NAD-dependent term since SIRT2 is a class III HDAC. Proposed replacements: histone deacetylase activity, NAD-dependent Supporting Evidence: PMID:17488717 2007 May 8. Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation.
GO:0005634 nucleus	IDA PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox ...	ACCEPT	Summary: Nuclear SIRT2 interacts with HOXA10 transcription factor. Reason: Confirms nuclear functions of SIRT2. Supporting Evidence: PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10.
GO:0005634 nucleus	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 accumulates in nucleus upon LMB treatment or during mitosis. Reason: Key study on nuclear shuttling. Supporting Evidence: PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis.
GO:0005737 cytoplasm	IDA PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox ...	ACCEPT	Summary: Cytoplasmic localization observed. Reason: Consistent with other studies. Supporting Evidence: PMID:15213244 Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10.
GO:0005737 cytoplasm	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 predominantly cytoplasmic during interphase due to active nuclear export. Reason: Key study characterizing SIRT2 localization dynamics. Supporting Evidence: PMID:17726514 SIRT2 was exclusively cytoplasmic in 99.5% of cells
GO:0005813 centrosome	IDA PMID:17488717 Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dep...	ACCEPT	Summary: SIRT2 localizes to centrosome, phosphorylated by CDK1. Reason: Mitotic localization confirmed. Supporting Evidence: PMID:17488717 2007 May 8. Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation.
GO:0005813 centrosome	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 enriched at centrosome during prophase. Reason: Well-documented mitotic localization. Supporting Evidence: PMID:17726514 During early prophase, endogenous SIRT2 became enriched at the centrosome
GO:0005814 centriole	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 concentrated at centrioles during metaphase. Reason: Detailed mitotic localization study. Supporting Evidence: PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis.
GO:0005819 spindle	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 spreads along spindle fibers during metaphase. Reason: Consistent with tubulin deacetylase function. Supporting Evidence: PMID:17726514 At metaphase, SIRT2 remained concentrated in the centrioles and spread along the spindle fibers
GO:0030496 midbody	IDA PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 localizes to midbody during cytokinesis, colocalizing with Aurora B. Reason: Critical localization for cytokinesis function. Supporting Evidence: PMID:17726514 during cytokinesis, SIRT2 associated with the midbody
GO:0048471 perinuclear region of cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Perinuclear localization pattern. Reason: May reflect centrosomal/MTOC association.
GO:0051726 regulation of cell cycle	IMP PMID:17726514 Interphase nucleo-cytoplasmic shuttling and localization of ...	ACCEPT	Summary: SIRT2 overexpression affects mitotic progression and causes multinucleation. Reason: Core function of SIRT2 in cell cycle regulation. Supporting Evidence: PMID:17726514 Overexpression of wild-type GFP-SIRT2 increased by 3-fold... the number of cells containing 2 or more nuclei, suggesting that SIRT2 contributes to the proper progression through mitosis
GO:0021762 substantia nigra development	HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in...	UNDECIDED	Summary: SIRT2 detected in substantia nigra proteomics study comparing neurodegenerative diseases. Reason: Expression-based annotation from disease study. Does not demonstrate direct role in substantia nigra development. Supporting Evidence: PMID:22926577 2012 Aug 28. Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.
GO:0034983 peptidyl-lysine deacetylation	IDA PMID:23932781 Acetylation stabilizes ATP-citrate lyase to promote lipid bi...	ACCEPT	Summary: SIRT2 deacetylates ACLY at specific lysine residues. Reason: Core biological process with specific substrate. Supporting Evidence: PMID:23932781 2013 Aug 8. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IMP PMID:21841822 Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-media...	KEEP AS NON CORE	Summary: SIRT2 deacetylates FOXO3, leading to its ubiquitination and degradation. Reason: Indirect effect on protein stability through deacetylation. Supporting Evidence: PMID:21841822 Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.
GO:0008270 zinc ion binding	IDA PMID:11427894 Structure of the histone deacetylase SIRT2	ACCEPT	Summary: Crystal structure reveals zinc-binding module essential for SIRT2 structure. Reason: Structurally confirmed - zinc binding is required for proper folding. Supporting Evidence: PMID:11427894 a smaller domain composed of a helical module and a zinc-binding module
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:11427894 Structure of the histone deacetylase SIRT2	ACCEPT	Summary: Crystal structure and mutagenesis confirm NAD-dependent histone deacetylase activity. Reason: Foundational structural study establishing SIRT2 enzymatic mechanism. Supporting Evidence: PMID:11427894 Structure of the histone deacetylase SIRT2.
GO:0070403 NAD+ binding	IDA PMID:11427894 Structure of the histone deacetylase SIRT2	ACCEPT	Summary: NAD-binding domain structurally characterized in SIRT2. Reason: Essential cofactor binding confirmed by crystal structure. Supporting Evidence: PMID:11427894 Structure of the histone deacetylase SIRT2.
GO:0005737 cytoplasm	IDA PMID:16079181 Evolutionarily conserved and nonconserved cellular localizat...	ACCEPT	Summary: Comparative study confirming SIRT2 cytoplasmic localization. Reason: Systematic characterization of sirtuin localization. Supporting Evidence: PMID:16079181 2005 Aug 3. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.
GO:0033558 protein lysine deacetylase activity	IDA PMID:17172643 Multiple histone deacetylases and the CREB-binding protein r...	ACCEPT	Summary: Broad protein deacetylase activity demonstrated. Reason: SIRT2 deacetylates many non-histone substrates, making this general term appropriate. Supporting Evidence: PMID:17172643 2006 Dec 17. Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing.
GO:0003950 NAD+ poly-ADP-ribosyltransferase activity	TAS NOT PMID:17456799 Sirtuin functions in health and disease.	ACCEPT	Summary: This is a NOT annotation indicating SIRT2 does not have NAD+ poly-ADP- ribosyltransferase activity. Reason: The GOA record uses a NOT qualifier for this activity; we accept the negated annotation. Supporting Evidence: PMID:17456799 Apr 24. Sirtuin functions in health and disease.
GO:0005737 cytoplasm	IDA PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	ACCEPT	Summary: Cytoplasmic SIRT2 interacts with cell cycle regulators. Reason: Functional cytoplasmic localization. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0005874 microtubule	IDA PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	ACCEPT	Summary: SIRT2 associates with microtubules as tubulin deacetylase. Reason: Foundational study on SIRT2-microtubule association. Supporting Evidence: PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
GO:0007096 regulation of exit from mitosis	NAS PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	ACCEPT	Summary: SIRT2 regulates mitotic exit through CDC14B interaction. Reason: Core cell cycle function of SIRT2. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	ACCEPT	Summary: SIRT2 histone deacetylase activity in context of cell cycle regulation. Reason: Core function confirmed with cellular substrates. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0035035 histone acetyltransferase binding	IPI PMID:12887892 Sir2 regulates skeletal muscle differentiation	ACCEPT	Summary: SIRT2 interacts with PCAF acetyltransferase. Reason: Documented regulatory interaction with opposing enzyme. Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0042325 regulation of phosphorylation	NAS PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	KEEP AS NON CORE	Summary: SIRT2 affects phosphorylation through phosphatase interactions. Reason: Indirect effect through CDC14B interaction. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0042826 histone deacetylase binding	IPI PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	ACCEPT	Summary: SIRT2 interacts with HDAC6 in tubulin deacetylation complex. Reason: Documented interaction with class II HDAC. Supporting Evidence: PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
GO:0042903 tubulin deacetylase activity	IDA PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	ACCEPT	Summary: Original demonstration of SIRT2 tubulin deacetylase activity. Reason: Foundational paper establishing SIRT2 as major tubulin deacetylase. Supporting Evidence: PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
GO:0043130 ubiquitin binding	IDA PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	KEEP AS NON CORE	Summary: SIRT2 interacts with polyubiquitinated proteins. Reason: Documented but functional significance unclear. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0045843 negative regulation of striated muscle tissue development	IDA PMID:12887892 Sir2 regulates skeletal muscle differentiation	KEEP AS NON CORE	Summary: SIRT2 inhibits muscle differentiation through MyoD deacetylation. Reason: Tissue-specific developmental function. Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:12887892 Sir2 regulates skeletal muscle differentiation	KEEP AS NON CORE	Summary: SIRT2 represses MyoD-dependent transcription. Reason: Indirect transcriptional effect through substrate deacetylation. Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0051775 response to redox state	NAS PMID:12887892 Sir2 regulates skeletal muscle differentiation	ACCEPT	Summary: SIRT2 activity influenced by cellular NAD+/NADH ratio. Reason: NAD-dependent activity inherently links SIRT2 to cellular redox state. Supporting Evidence: PMID:12887892 Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
GO:0000183 rDNA heterochromatin formation	NAS PMID:11427894 Structure of the histone deacetylase SIRT2	KEEP AS NON CORE	Summary: Extrapolated from yeast Sir2 function mentioned in structural paper. Reason: Based on yeast homolog function. Human SIRT2 is primarily cytoplasmic. Supporting Evidence: PMID:11427894 Structure of the histone deacetylase SIRT2.
GO:0031507 heterochromatin formation	NAS PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	KEEP AS NON CORE	Summary: SIRT2 role in heterochromatin from H4K16 deacetylation. Reason: Related to chromatin function but primary role is during mitosis. Supporting Evidence: PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
GO:0031509 subtelomeric heterochromatin formation	NAS PMID:11427894 Structure of the histone deacetylase SIRT2	UNDECIDED	Summary: Extrapolated from yeast Sir2 telomeric silencing function. Reason: Limited direct evidence for human SIRT2 in telomeric silencing. Supporting Evidence: PMID:11427894 Structure of the histone deacetylase SIRT2.
GO:0031115 negative regulation of microtubule polymerization	IDA PMID:23886946 Furry promotes acetylation of microtubules in the mitotic sp...	NEW	Summary: SIRT2 deacetylates alpha-tubulin at K40, which destabilizes microtubules. Reason: Direct consequence of SIRT2 tubulin deacetylase activity - deacetylation promotes microtubule depolymerization. Supporting Evidence: PMID:23886946 AGK2, a specific inhibitor of SIRT2, increased the level of MT acetylation in the mitotic spindle, indicating that SIRT2 is involved in the deacetylation of spindle MTs
GO:0016192 vesicle-mediated transport	IMP PMID:32103017 NMT1 and NMT2 are lysine myristoyltransferases regulating th...	NEW	Summary: SIRT2 demyristoylates ARF6 to regulate vesicle trafficking. Reason: Demyristoylation of ARF6 by SIRT2 affects membrane trafficking and vesicle formation. Supporting Evidence: PMID:32103017 We demonstrate that the NAD+-dependent deacylase SIRT2 removes the myristoyl group
GO:0030261 chromosome condensation	IMP PMID:12697818 Role for human SIRT2 NAD-dependent deacetylase activity in c...	NEW	Summary: SIRT2 deacetylates H4K16 during G2/M transition for chromosome condensation. Reason: H4K16 deacetylation by SIRT2 is required for proper chromosome condensation during mitosis. Supporting Evidence: PMID:12697818 The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G(2)/M transition of the cell cycle
GO:0073163 E-cadherin localization to cell surface	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:25704306 The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group doi:10.1073/pnas.2319833121 Sirt2 inhibition shifts ARF6 dynamics to increase E-cadherin at the cell surface and improve epithelial barrier function
GO:0042742 defense response to bacterium	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: doi:10.1038/s41467-022-32227-x Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation; SIRT2 removes lysine fatty acylations installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family members and CHMP5 doi:10.1172/jci158978 FLS-359 allosteric SIRT2 inhibitor exhibits broad-spectrum antiviral activity
GO:0051607 defense response to virus	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: doi:10.1038/s41467-022-32227-x Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation; SIRT2 removes lysine fatty acylations installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family members and CHMP5 doi:10.1172/jci158978 FLS-359 allosteric SIRT2 inhibitor exhibits broad-spectrum antiviral activity

Core Functions

Deacetylates alpha-tubulin at K40 in cytoplasm, regulating microtubule stability and dynamics

Molecular Function:

tubulin deacetylase activity

Directly Involved In:

negative regulation of microtubule polymerization

Cellular Locations:

cytosol microtubule

Substrates:

TUBA1A (alpha-tubulin)

Supporting Evidence:

PMID:11427894
The 1.7 A crystal structure of the 323 amino acid catalytic core of human SIRT2
PMID:23886946
SIRT2 tubulin deacetylase activity demonstrated in mitotic spindle context

Demyristoylates ARF6 at K3, regulating membrane trafficking and E-cadherin recycling to plasma membrane

Molecular Function:

NAD-dependent protein demyristoylase activity

Directly Involved In:

vesicle-mediated transport E-cadherin localization to cell surface

Cellular Locations:

cytosol

Substrates:

ARF6 (ADP-ribosylation factor 6)

Supporting Evidence:

PMID:25704306
The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group
doi:10.1073/pnas.2319833121
Sirt2 inhibition shifts ARF6 dynamics to increase E-cadherin at the cell surface and improve epithelial barrier function

Deacetylates histone H4K16 during mitosis, promoting chromatin condensation for proper chromosome segregation

Molecular Function:

histone H4K16 deacetylase activity, NAD-dependent

Directly Involved In:

chromosome condensation cell division

Cellular Locations:

chromosome nucleus

Substrates:

H4 histone

Supporting Evidence:

PMID:16648462
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
PMID:17726514
SIRT2 contributes to the proper progression through mitosis... During the cell cycle, SIRT2 becomes enriched in the nucleus

Removes lysine fatty-acyl modifications installed by bacterial effectors, counteracting pathogen virulence mechanisms

Molecular Function:

NAD-dependent protein demyristoylase activity

Directly Involved In:

defense response to bacterium defense response to virus

Cellular Locations:

cytosol

Supporting Evidence:

doi:10.1038/s41467-022-32227-x
Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation; SIRT2 removes lysine fatty acylations installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family members and CHMP5
doi:10.1172/jci158978
FLS-359 allosteric SIRT2 inhibitor exhibits broad-spectrum antiviral activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10381378

Characterization of five human cDNAs with homology to the yeast SIR2 gene

SIRT2 identified as one of five human sirtuins

"Here five human sirtuin cDNAs are characterized. The SIRT1 sequence has the closest homology to the S. cerevisiae Sir2p."
Demonstrated weak ADP-ribosyltransferase activity

"Recombinant E. coli cobB and human SIRT2 sirtuin proteins were able to cause radioactivity to be transferred from [32P]NAD to bovine serum albumin (BSA)."

PMID:11427894

Structure of the histone deacetylase SIRT2

Crystal structure at 1.7A resolution

"The 1.7 A crystal structure of the 323 amino acid catalytic core of human SIRT2, a homolog of yeast Sir2, reveals an NAD-binding domain, which is a variant of the Rossmann fold, and a smaller domain composed of a helical module and a zinc-binding module."
NAD-binding Rossmann fold domain identified

"The 1.7 A crystal structure of the 323 amino acid catalytic core of human SIRT2, a homolog of yeast Sir2, reveals an NAD-binding domain, which is a variant of the Rossmann fold"
Zinc-binding module essential for structure

"a smaller domain composed of a helical module and a zinc-binding module"

PMID:12620231

The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.

SIRT2 deacetylates alpha-tubulin at K40

"SIRT2 deacetylates lysine-40 of alpha-tubulin both in vitro and in vivo."
Functions with HDAC6 in tubulin deacetylation

"SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase."

PMID:12697818

Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit

SIRT2 regulates mitotic exit

"Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis."
Interacts with CDC14B phosphatase

"Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein."

PMID:12887892

Sir2 regulates skeletal muscle differentiation

SIRT2 inhibits MyoD-dependent muscle differentiation

"Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation."
Interacts with PCAF acetyltransferase

"Sir2 forms a complex with the acetyltransferase PCAF and MyoD"

PMID:16648462

SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis

H4K16 is preferred histone substrate

"SirT2 and its yeast counterpart Hst2 have a strong preference for histone H4K16Ac in their deacetylation activity in vitro and in vivo."
Nuclear during mitosis for chromatin condensation

"We have pinpointed the decrease in global levels of H4K16Ac during the mammalian cell cycle to the G2/M transition that coincides with SirT2 localization on chromatin."

PMID:17488717

Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation.

SIRT2 phosphorylated at Ser368 by CDK1

"SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1"
Dephosphorylated by CDC14A/B

"dephosphorylated by the phosphatases CDC14A and CDC14B"

PMID:17726514

Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis

CRM1-dependent nuclear export

"These results indicate that SIRT2 is actively exported from the nucleus in a Crm1-dependent manner."
Localizes to centrosome, spindle, midbody during mitosis

"During early prophase, endogenous SIRT2 became enriched at the centrosome demonstrated by its colocalization with Aurora A, a mitotic regulatory kinase also found on the centrosomes"
Interacts with Aurora A and Aurora B

"Utilizying coimmunoprecipitation experiments with FLAG-tagged SIRT2 and Myc-tagged Aurora A indicate that these two proteins interact in a mutliprotein complex"

PMID:18722353

Acetylation of Sirt2 by p300 attenuates its deacetylase activity

p300 acetylates and inhibits SIRT2

"p300 interacts with Sirt2, a member of the Sir2 family, and triggers the acetylation and subsequent down-regulation of the deacetylation activity of Sirt2"
Affects p53-dependent transcription

"the acetylation of Sirt2 by p300 relieves the inhibitory effect of Sirt2 on the transcriptional activity of p53"

PMID:20543840

Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.

SIRT2 deacetylates FOXO1

"FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD(+)-dependent histone deacetylase"
Regulates autophagy through FOXO1-ATG7 interaction

"the acetylated FoxO1 bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death"

PMID:21081649

SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310.

SIRT2 deacetylates p65 at K310

"SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo at Lys310."
Regulates NF-kB-dependent gene expression

"p65 is deacetylated by SIRT2 in the cytoplasm to regulate the expression of specific NF-κB-dependent genes."

PMID:21949390

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.

SIRT2 deacetylates Par-3

"Sirt2 deacetylates Par-3, a master regulator of cell polarity"
Regulates Schwann cell polarity and myelination

"The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation."

PMID:23908241

A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection.

SIRT2 translocates to nucleus during Listeria infection

"during infection with the bacterium Listeria monocytogenes, the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus, in a manner dependent on the bacterial factor InlB"
Deacetylates H3K18 at gene promoters

"SIRT2 associates with the transcription start site of a subset of genes repressed during infection and deacetylates histone H3 on lysine 18 (H3K18)"

PMID:23932781

Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.

SIRT2 deacetylates ACLY at K540/546/554

"ACLY is acetylated at lysine residues 540, 546, and 554 (3K)"
Destabilizes ACLY by promoting ubiquitination

"the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY"

PMID:24681946

SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.

SIRT2 deacetylates HIF1A at K709

"SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α"
Promotes HIF1A hydroxylation and degradation

"Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination."

PMID:25704306

Efficient demyristoylase activity of SIRT2

kcat/Km for demyristoylation higher than deacetylation

"The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group."
Crystal structure with thiomyristoyl peptide

"The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group."
Large hydrophobic pocket accommodates fatty acyl groups

"The thiomyristoyl group of BHJH-TM1 is accommodated by a hydrophobic pocket formed by several hydrophobic residues of SIRT2, including Ile93, Phe96, Phe119, Phe131, Leu134, Leu138, Phe143, Ile169, Phe190, Ile232, and Phe234"

PMID:32103017

NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.

SIRT2 removes myristoyl and palmitoyl groups from lysines

"We demonstrate that the NAD+-dependent deacylase SIRT2 removes the myristoyl group"

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry

PMID:21653829

Protein interactome reveals converging molecular pathways among autism disorders.

PMID:24769394

Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

SIRT2 deacetylates G6PD at lysine 403 in response to oxidative stress to activate the pentose phosphate pathway

"cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage"
K403 acetylation of G6PD prevents active dimer formation resulting in complete loss of enzymatic activity

"The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity."

PMID:24825348

SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.

SIRT2 maintains BubR1 levels by deacetylating lysine-668, counteracting CBP acetyltransferase

"Here, we show that the loss of BubR1 levels with age is due to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP"
NAD(+) precursor NMN treatment increases BubR1 abundance in vivo through SIRT2

"Overexpression of SIRT2 or treatment of mice with the NAD(+) precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:15213244

Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10.

SIRT2 interacts with HOXA10 as identified by two-hybrid screen and confirmed by co-immunoprecipitation

"Here we show for the first time that SIRT2 interacts with the homeobox transcription factor, HOXA10, which was identified in a two-hybrid screen. Interactions were confirmed by co-immunoprecipitation from in vitro translations as well as in human cell-free extracts."
SIRT2 interaction with HOXA10 suggests a role in mammalian development

"Taken together with mouse knockout studies, our results raise the intriguing possibility that SIRT2 plays a role in mammalian development."

PMID:27512957

Oncogenic microtubule hyperacetylation through BEX4-mediated sirtuin 2 inhibition.

BEX4 interacts with alpha-tubulin and SIRT2 to inhibit SIRT2-mediated tubulin deacetylation

"Among BEX proteins, BEX4 localizes to microtubules and spindle poles, and interacts with α-tubulin (α-TUB) and sirtuin 2 (SIRT2). The overexpression of BEX4 leads to the hyperacetylation of α-TUB by inhibiting SIRT2-mediated deacetylation."
SIRT2 wild-type but not H187Y deacetylase-dead mutant forms complex with BEX4

"A subsequent pull-down assay showed that SIRT2 wild-type, but not the H187Y deacetylase activity dead mutant, formed a complex with BEX4, whereas both SIRT2 wild-type and H187Y mutants interact with α-TUB"
BEX4 competes with SIRT2 for alpha-tubulin binding through its middle domain

"Pull-down assays revealed that α-TUB bound to GST-BEX4 C and very weakly to GST-BEX4 M. Interestingly, GST-BEX4 M only formed a complex with SIRT2"

PMID:17172643

Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3-end processing.

Reactome:R-HSA-2995410

Reactome pathway: Mitotic nuclear membrane reassembly

Reactome:R-HSA-9667952

Reactome pathway: SIRT2 deacetylates ANKLE2

PMID:34961760

Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.

PMID:30154464

Lysine benzoylation is a histone mark regulated by SIRT2.

SIRT2 is the only HDAC family member that removes histone lysine benzoylation (Kbz) both in vitro and in vivo

"we demonstrate that SIRT2, a NAD+-dependent protein deacetylase, removes histone Kbz both in vitro and in vivo"
SIRT2 has debenzoylase activity with Kcat/Km approximately 1/6 of deacetylase activity

"Kcat/Km for debenzoylation was approximately 1/6 of that for deacetylation"
Loss of SIRT2 increases global histone Kbz levels especially on H3 and H2B

"By examining core histone Kbz levels in Sirt2+/+ (wild-type (WT)) and Sirt2−/− (knockout (KO)) mouse embryonic fibroblast (MEF) cells, we found that loss of SIRT2 expression was associated with increased Kbz levels, especially on H3 and H2B proteins"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:17456799

Sirtuin functions in health and disease.

PMID:15126506

FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).

PMID:23886946

Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase.

PMID:22926577

Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.

PMID:21841822

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.

PMID:16079181

Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.

file:human/SIRT2/SIRT2-deep-research-falcon.md

Deep research on SIRT2 function

Suggested Experiments

Experiment: Proteomics to identify SIRT2 demyristoylation substrates in cells

Experiment: Live-cell imaging to characterize SIRT2 localization dynamics during cell cycle

Experiment: Structure-function studies to separate deacetylase and defatty-acylase activities

📚 Additional Documentation

Deep Research Falcon

(SIRT2-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-23T14:24:47.516188'
end_time: '2025-12-23T14:35:19.069793'
duration_seconds: 631.55
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: SIRT2
gene_symbol: SIRT2
uniprot_accession: Q8IXJ6
protein_description: 'RecName: Full=NAD-dependent protein deacetylase sirtuin-2;
EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:11483616,
ECO:0000269|PubMed:11812793, ECO:0000269|PubMed:16648462, ECO:0000269|PubMed:18722353,
ECO:0000269|PubMed:24177535}; AltName: Full=NAD-dependent protein defatty-acylase
sirtuin-2 {ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:25704306, ECO:0000269|PubMed:29239724,
ECO:0000269|PubMed:32103017}; AltName: Full=Regulatory protein SIR2 homolog 2;
AltName: Full=SIR2-like protein 2;'
gene_info: Name=SIRT2; Synonyms=SIR2L, SIR2L2;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the sirtuin family. Class I subfamily.
protein_domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases.
(IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I.
(IPR017328)
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citation_count: 41

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q8IXJ6
Protein Description: RecName: Full=NAD-dependent protein deacetylase sirtuin-2; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:11483616, ECO:0000269|PubMed:11812793, ECO:0000269|PubMed:16648462, ECO:0000269|PubMed:18722353, ECO:0000269|PubMed:24177535}; AltName: Full=NAD-dependent protein defatty-acylase sirtuin-2 {ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:25704306, ECO:0000269|PubMed:29239724, ECO:0000269|PubMed:32103017}; AltName: Full=Regulatory protein SIR2 homolog 2; AltName: Full=SIR2-like protein 2;
Gene Information: Name=SIRT2; Synonyms=SIR2L, SIR2L2;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I. (IPR017328)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SIRT2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SIRT2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SIRT2 (gene ID: SIRT2, UniProt: Q8IXJ6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q8IXJ6
Protein Description: RecName: Full=NAD-dependent protein deacetylase sirtuin-2; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:11483616, ECO:0000269|PubMed:11812793, ECO:0000269|PubMed:16648462, ECO:0000269|PubMed:18722353, ECO:0000269|PubMed:24177535}; AltName: Full=NAD-dependent protein defatty-acylase sirtuin-2 {ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:25704306, ECO:0000269|PubMed:29239724, ECO:0000269|PubMed:32103017}; AltName: Full=Regulatory protein SIR2 homolog 2; AltName: Full=SIR2-like protein 2;
Gene Information: Name=SIRT2; Synonyms=SIR2L, SIR2L2;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I. (IPR017328)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SIRT2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SIRT2 (gene ID: SIRT2, UniProt: Q8IXJ6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human SIRT2 (UniProt Q8IXJ6)

Executive verification of identity and scope
- Target: SIRT2 (sirtuin-2), human NAD+-dependent lysine deacylase in the class I sirtuin family (UniProt Q8IXJ6). Literature retrieved below consistently refers to human SIRT2, matching the NAD-dependent deacetylase/defatty-acylase description and sirtuin family/domain architecture; no symbol ambiguity identified. SIRT2 is predominantly cytosolic with nucleo-cytoplasmic shuttling, consistent with Class I sirtuin features (reviewed and evidenced below) (garmendiaberges2023ageassociatedchangesof pages 2-4, shenk2024drugstargetingsirtuin pages 4-6).

1) Key concepts and definitions
- Enzymatic class and mechanism: SIRT2 is a member of the NAD+-dependent sirtuin family that removes acyl groups from ε-lysine side chains via a catalytic mechanism that couples acyl-lysine to NAD+, releasing nicotinamide and producing 2′-O-acyl-ADP-ribose with the deacylated lysine. Structural pockets A/B/C bind NAD+/nicotinamide, and the extended C (EC) pocket accommodates long-chain acyl groups, underpinning selectivity and allosteric modulation (Pharmaceuticals review, 2024) (URL: https://doi.org/10.3390/ph17101298; Sep 2024) (shenk2024drugstargetingsirtuin pages 6-8).
- Activities and substrate scope: SIRT2 catalyzes lysine deacetylation and defatty-acylation (including demyristoylation); it can remove diverse acyl groups (acetyl to long-chain acyls such as myristoyl) (2024 review; 2024 HTRF screen) (URL: https://doi.org/10.3390/ph17101298; Sep 2024; URL: https://doi.org/10.1371/journal.pone.0305000; Jun 2024) (shenk2024drugstargetingsirtuin pages 6-8, yang2024ahomogeneoustimeresolved pages 18-19). Canonical substrates include α-tubulin K40 (microtubules) and histone sites (e.g., H4K16) among others; the EC pocket explains SIRT2’s efficient demyristoylase activity (2024 J Med Chem SAR; 2024 review) (URL: https://doi.org/10.1021/acs.jmedchem.4c00229; Jun 2024; URL: https://doi.org/10.3390/ph17101298; Sep 2024) (colcerasa2024structureactivitystudiesof pages 54-56, shenk2024drugstargetingsirtuin pages 6-8).
- Cellular localization: SIRT2 is largely cytoplasmic but shuttles to the nucleus (e.g., during mitosis or infection). Isoforms differ in localization: major isoforms are cytosolic and shuttling; a nuclear isoform (SIRT2.5) lacks a nuclear export sequence and is inactive in standard biochemical assays (review, 2024) (URL: https://doi.org/10.3390/ph17101298; Sep 2024) (shenk2024drugstargetingsirtuin pages 4-6). Age-focused review and infection studies support nucleo-cytoplasmic dynamics and stress- or signaling-dependent relocalization (URL: https://doi.org/10.3390/biology12121476; Nov 2023) (garmendiaberges2023ageassociatedchangesof pages 2-4).

2) Recent developments and latest research (2023–2024 priority)
- Allosteric, substrate-selective SIRT2 inhibition with broad-spectrum antiviral activity: FLS-359 is a SIRT2-selective allosteric inhibitor/modulator that binds in the EC pocket. It partially inhibits deacetylation without blocking demyristoylation and exhibits broad antiviral activity in vitro (e.g., SARS‑CoV‑2 EC50 ≈ 0.3 μM; Zika 0.4 μM; HCMV 0.5 μM; Influenza A ~1.2 μM; RSV 6.7 μM) and reduces HCMV in two humanized mouse models (J Clin Invest, 2023; Pharmaceuticals, 2024) (URLs: https://doi.org/10.1172/jci158978; Jun 2023; https://doi.org/10.3390/ph17101298; Sep 2024) (roche2023anallostericinhibitor pages 3-5, roche2023anallostericinhibitor pages 8-10, shenk2024drugstargetingsirtuin pages 8-9, shenk2024drugstargetingsirtuin pages 2-4).
- SIRT2 inhibition in inflammatory bowel disease (IBD) models: Small-molecule Sirt2 inhibitors improved gut epithelial barrier integrity and protected mice from DSS-induced colitis, mechanistically via modulating the ARF6 fatty-acylation cycle and E-cadherin trafficking. Genetic vs pharmacologic perturbation emphasized substrate-selective inhibition advantages (PNAS, 2024) (URL: https://doi.org/10.1073/pnas.2319833121; Apr 2024) (hou2024sirt2inhibitionimproves pages 3-5).
- Enzyme screening and modality innovation: A 2024 homogeneous time-resolved fluorescence (HTRF) binding assay was developed to identify SIRT2 deacetylase versus demyristoylase inhibitors, discovering a compound with dual inhibition (IC50 deacetylase 7 μM; demyristoylase 37 μM) and detecting deacetylation-specific inhibitors (PLOS ONE, 2024) (URL: https://doi.org/10.1371/journal.pone.0305000; Jun 2024) (yang2024ahomogeneoustimeresolved pages 18-19). Structure–activity studies in 2024 characterized new selective chemotypes for SIRT2 deacetylase inhibition, including co-crystal structural confirmation and cellular activity (J Med Chem, 2024) (URL: https://doi.org/10.1021/acs.jmedchem.4c00229; Jun 2024) (colcerasa2024structureactivitystudiesof pages 54-56).
- Viral cell-cycle control: SIRT2 deacetylase activity supports early stages of human cytomegalovirus (HCMV) replication through regulation of CDK2 acetylation and the G1–S transition; pharmacologic inhibition with AGK2 at 2.5 μM early post‑infection impairs viral replication (mSystems, 2023) (URL: https://doi.org/10.1128/msystems.00510-23; Dec 2023) (betsinger2023sirtuin2promotes pages 5-7).

3) Current applications and real-world implementations
- Host-directed antivirals: FLS-359 and related SIRT2 modulators provide broad-spectrum antiviral activities across DNA and RNA viruses, with in vivo efficacy in HCMV humanized mouse models, and favorable oral PK in mice (t1/2 ~6 h; Cmax 89 μM; AUC 713 μM·h/mL at 50 mg/kg PO) (JCI 2023; Pharmaceuticals 2024) (URLs: https://doi.org/10.1172/jci158978; Jun 2023; https://doi.org/10.3390/ph17101298; Sep 2024) (roche2023anallostericinhibitor pages 8-10, shenk2024drugstargetingsirtuin pages 8-9).
- Inflammation and barrier disease: In IBD models, Sirt2 inhibitors and modulation of the NMT–SIRT2–ARF6 axis improved epithelial integrity and reduced DSS colitis severity, highlighting translation potential for gut barrier diseases (PNAS, 2024) (URL: https://doi.org/10.1073/pnas.2319833121; Apr 2024) (hou2024sirt2inhibitionimproves pages 3-5).
- Tool compounds and screening platforms: Dual-activity HTS assays and SAR-driven chemotypes broaden the toolbox for selectively modulating SIRT2’s deacetylase versus defatty-acylase activities, enabling substrate-biased pharmacology (PLOS ONE 2024; J Med Chem 2024) (URLs: https://doi.org/10.1371/journal.pone.0305000; https://doi.org/10.1021/acs.jmedchem.4c00229) (yang2024ahomogeneoustimeresolved pages 18-19, colcerasa2024structureactivitystudiesof pages 54-56).

4) Expert opinions and analysis from authoritative sources
- Substrate-selective modulation is advantageous: Reviews and structural studies indicate that partial, substrate-selective allosteric modulation (e.g., inhibiting deacetylation but sparing demyristoylation) can produce beneficial phenotypes distinct from genetic knockouts, with improved tolerability and efficacy in host-directed anti-infective strategies (JCI 2023; Pharmaceuticals 2024) (URLs: https://doi.org/10.1172/jci158978; https://doi.org/10.3390/ph17101298) (roche2023anallostericinhibitor pages 8-10, shenk2024drugstargetingsirtuin pages 8-9). The IBD study similarly emphasizes the divergence of inhibitor vs genetic phenotypes in vivo (PNAS 2024) (URL: https://doi.org/10.1073/pnas.2319833121) (hou2024sirt2inhibitionimproves pages 3-5).
- Context-dependent roles: Age-related and tissue-specific analyses show SIRT2 functions vary by compartment and physiological state; nuclear relocalization during infection reprograms host transcription, while cytosolic functions dominate microtubule regulation and membrane trafficking (Biology 2023; Pharmaceuticals 2024) (URLs: https://doi.org/10.3390/biology12121476; https://doi.org/10.3390/ph17101298) (garmendiaberges2023ageassociatedchangesof pages 2-4, shenk2024drugstargetingsirtuin pages 4-6, shenk2024drugstargetingsirtuin pages 11-12).

5) Relevant statistics and data from recent studies
- Enzyme inhibition quantitative data:
• FLS-359 SIRT2 deacetylase IC50 ≈ 3 μM (≫100 μM for SIRT1/3); partial inhibition persists at saturation; IC50 increased to ~7 μM when peptide substrate increased from 5 to 50 μM; thermal shift ΔTm +1.4°C at 6.25 μM and +2.0°C at 12.5 μM (JCI, 2023) (URL: https://doi.org/10.1172/jci158978; Jun 2023) (roche2023anallostericinhibitor pages 2-3, roche2023anallostericinhibitor pages 1-2).
• HTRF screening yielded a dual-activity hit: deacetylase IC50 7 μM and demyristoylase IC50 37 μM (PLOS ONE, 2024) (URL: https://doi.org/10.1371/journal.pone.0305000; Jun 2024) (yang2024ahomogeneoustimeresolved pages 18-19).
- Antiviral potency and PK:
• FLS-359 antiviral IC50/EC50 examples: SARS‑CoV‑2 ~0.3 μM (CC50 15.8 μM, SI ~53); Zika ~0.4 μM (CC50 41.6 μM, SI ~104); HCMV ~0.5 μM (cell-to-cell spread); Influenza A ~1.2 μM (CC50 >100 μM); RSV 6.7 μM (review table) (JCI, 2023; Pharm, 2024) (URLs: https://doi.org/10.1172/jci158978; https://doi.org/10.3390/ph17101298) (roche2023anallostericinhibitor pages 3-5, shenk2024drugstargetingsirtuin pages 2-4).
• Mouse PK: FLS-359 t1/2 ~6 h; Cmax 89 μM; AUC 713 μM·h/mL at 50 mg/kg PO; tolerated at 50 mg/kg b.i.d. ×14 days without adverse signs (Pharm, 2024) (URL: https://doi.org/10.3390/ph17101298; Sep 2024) (shenk2024drugstargetingsirtuin pages 8-9).
• HCMV dependency window: AGK2 (2.5 μM) inhibits replication when added before 24 h post-infection; later addition less effective (mSystems, 2023) (URL: https://doi.org/10.1128/msystems.00510-23; Dec 2023) (betsinger2023sirtuin2promotes pages 5-7).
- Barrier/inflammation endpoints (IBD): Sirt2 inhibition or Sirt2 knockdown increased epithelial TEER, reduced paracellular permeability (Lucifer Yellow), and decreased serum FITC-dextran leakage in DSS-treated mice; NMT inhibitor IMP-1088 at 5 mg/kg protected DSS mice and at 0.1 μM reduced ARF6 fatty-acylation and ARF6-GTP in Caco-2 cells (PNAS, 2024) (URL: https://doi.org/10.1073/pnas.2319833121; Apr 2024) (hou2024sirt2inhibitionimproves pages 3-5).

Functional and mechanistic roles
A) Enzymatic activities and substrate specificity
- Dual activity: SIRT2 is both a lysine deacetylase and a potent lysine defatty-acylase (including demyristoylase). Structural analyses show an EC/selectivity pocket that accommodates long-chain acyls; allosteric modulators can bias activity toward or against specific acyl substrates (2024 review; JCI 2023; HTRF screen 2024) (URLs: https://doi.org/10.3390/ph17101298; https://doi.org/10.1172/jci158978; https://doi.org/10.1371/journal.pone.0305000) (shenk2024drugstargetingsirtuin pages 6-8, roche2023anallostericinhibitor pages 8-10, yang2024ahomogeneoustimeresolved pages 18-19).
- Tubulin deacetylation: α-tubulin K40 deacetylation is a foundational SIRT2 function linking SIRT2 to microtubule stability and dynamics (2024 J Med Chem SAR review; age review) (URLs: https://doi.org/10.1021/acs.jmedchem.4c00229; https://doi.org/10.3390/biology12121476) (colcerasa2024structureactivitystudiesof pages 54-56, garmendiaberges2023ageassociatedchangesof pages 2-4).
- Defatty-acylation of host proteins: SIRT2 removes lysine fatty acylations installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family members and CHMP5; SIRT2 is transcriptionally induced under Golgi stress via CREB3, enhancing host defense (Nat Commun, 2022) (URL: https://doi.org/10.1038/s41467-022-32227-x; Aug 2022) (wang2022golgistressinduces pages 4-6, wang2022golgistressinduces pages 6-8, wang2022golgistressinduces pages 2-4).
- ARF6 K3 myristoylation cycle: NMT1/2 install lysine myristoylation on ARF6 K3, promoting membrane association during the GTPase cycle; SIRT2 removes this myristoyl group. Pharmacologic Sirt2 inhibition shifts ARF6 dynamics to increase E-cadherin at the cell surface and improve epithelial barrier function (PNAS, 2024) (URL: https://doi.org/10.1073/pnas.2319833121; Apr 2024) (hou2024sirt2inhibitionimproves pages 3-5).
- CDK2 acetylation: SIRT2 deacetylase activity modulates CDK2 K6 acetylation and controls the G1–S transition, supporting early HCMV replication (mSystems, 2023) (URL: https://doi.org/10.1128/msystems.00510-23; Dec 2023) (betsinger2023sirtuin2promotes pages 5-7).

B) Cellular localization and dynamics
- Predominantly cytosolic, associates with microtubules (α-tubulin). SIRT2 shuttles to the nucleus in mitosis and during certain infections, where it deacetylates histone H3K18 and reprograms host transcription; SIRT2 induction by Golgi stress via CREB3 increases cellular defatty-acylase capacity (2024 review; 2023 Biology; 2022 Nat Commun) (URLs: https://doi.org/10.3390/ph17101298; https://doi.org/10.3390/biology12121476; https://doi.org/10.1038/s41467-022-32227-x) (shenk2024drugstargetingsirtuin pages 4-6, garmendiaberges2023ageassociatedchangesof pages 2-4, wang2022golgistressinduces pages 2-4, shenk2024drugstargetingsirtuin pages 11-12).

C) Pathways and precise roles
- Cytoskeleton and membrane trafficking: Through α-tubulin deacetylation and ARF6 defatty-acylation, SIRT2 regulates microtubule stability, intracellular transport, and junctional trafficking (e.g., E-cadherin recycling), with barrier integrity consequences in gut epithelium (PNAS, 2024; J Med Chem 2024) (URLs: https://doi.org/10.1073/pnas.2319833121; https://doi.org/10.1021/acs.jmedchem.4c00229) (hou2024sirt2inhibitionimproves pages 3-5, colcerasa2024structureactivitystudiesof pages 54-56).
- Cell cycle: SIRT2 deacetylase activity influences G1–S transition via CDK2 K6 acetylation control during HCMV infection, and broader mitotic roles are consistent with earlier tubulin and chromatin substrate findings (mSystems, 2023) (URL: https://doi.org/10.1128/msystems.00510-23) (betsinger2023sirtuin2promotes pages 5-7).
- Immunity/host–pathogen interactions: SIRT2 is induced by pathogen-triggered Golgi stress and reverses bacterial effector-driven lysine fatty-acylation to bolster innate defense; in viral infection, allosteric SIRT2 modulation reduces yields across multiple virus families, with in vivo efficacy (Nat Commun 2022; JCI 2023; Pharmaceuticals 2024) (URLs: https://doi.org/10.1038/s41467-022-32227-x; https://doi.org/10.1172/jci158978; https://doi.org/10.3390/ph17101298) (wang2022golgistressinduces pages 6-8, roche2023anallostericinhibitor pages 8-10, shenk2024drugstargetingsirtuin pages 8-9).
- Metabolism and stress: Proteomic interaction/acetylome studies show SIRT2 engages with glycolytic and redox enzymes, and regulates metabolic acetylation programs without necessarily localizing inside mitochondria, indicative of indirect control (Biology 2023; Biomolecules 2024) (URLs: https://doi.org/10.3390/biology12121476; https://doi.org/10.3390/biom14091160) (garmendiaberges2023ageassociatedchangesof pages 2-4).

Strength of evidence and nuances
- Multiple convergent lines of evidence (enzyme biochemistry, X‑ray structures, cell biology, proteomics, and mouse models) establish SIRT2’s dual enzymatic roles and context-dependent functions. Notably, pharmacologic SIRT2 inhibition can yield different outcomes than genetic loss—consistent with substrate-selective/allosteric mechanisms—illustrated by antiviral and IBD models (JCI 2023; PNAS 2024; review 2024) (URLs: https://doi.org/10.1172/jci158978; https://doi.org/10.1073/pnas.2319833121; https://doi.org/10.3390/ph17101298) (roche2023anallostericinhibitor pages 8-10, hou2024sirt2inhibitionimproves pages 3-5, shenk2024drugstargetingsirtuin pages 8-9).

References with URLs and dates
- Roche et al., J Clin Invest, 2023: Allosteric SIRT2 inhibitor FLS-359; antiviral breadth; partial deacetylase inhibition; structural mode (URL: https://doi.org/10.1172/jci158978; Jun 2023) (roche2023anallostericinhibitor pages 8-10, roche2023anallostericinhibitor pages 1-2, roche2023anallostericinhibitor pages 3-5, roche2023anallostericinhibitor pages 2-3).
- Shenk, Kulp, Chiang, Pharmaceuticals, 2024: Review of SIRT2-targeted anti-infectives; EC pocket modulators; PK of FLS-359; isoforms/localization (URL: https://doi.org/10.3390/ph17101298; Sep 2024) (shenk2024drugstargetingsirtuin pages 19-21, shenk2024drugstargetingsirtuin pages 4-6, shenk2024drugstargetingsirtuin pages 6-8, shenk2024drugstargetingsirtuin pages 8-9, shenk2024drugstargetingsirtuin pages 2-4, shenk2024drugstargetingsirtuin pages 11-12).
- Hou et al., PNAS, 2024: Sirt2 inhibition protects from DSS colitis; ARF6 lysine myristoylation cycle; epithelial barrier integrity (URL: https://doi.org/10.1073/pnas.2319833121; Apr 2024) (hou2024sirt2inhibitionimproves pages 3-5).
- Betsinger et al., mSystems, 2023: SIRT2 deacetylase supports HCMV replication; CDK2 K6 acetylation; early infection window; AGK2 2.5 μM efficacy (URL: https://doi.org/10.1128/msystems.00510-23; Dec 2023) (betsinger2023sirtuin2promotes pages 5-7).
- Colcerasa et al., J Med Chem, 2024: Structure-activity for 1,2,4-oxadiazole-based SIRT2 inhibitors; deacetylase focus; co-crystal evidence (URL: https://doi.org/10.1021/acs.jmedchem.4c00229; Jun 2024) (colcerasa2024structureactivitystudiesof pages 54-56).
- Yang et al., PLOS ONE, 2024: HTRF screen distinguishing SIRT2 deacetylase vs demyristoylase inhibition; dual-activity hit (IC50 7 μM vs 37 μM) (URL: https://doi.org/10.1371/journal.pone.0305000; Jun 2024) (yang2024ahomogeneoustimeresolved pages 18-19).
- Wang et al., Nat Commun, 2022: Golgi stress–CREB3 induction of SIRT2; defatty-acylase counteraction of Shigella IcsB; in vivo susceptibility of Sirt2−/− mice (URL: https://doi.org/10.1038/s41467-022-32227-x; Aug 2022) (wang2022golgistressinduces pages 6-8, wang2022golgistressinduces pages 4-6, wang2022golgistressinduces pages 10-11, wang2022golgistressinduces pages 2-4).
- Garmendia-Berges et al., Biology, 2023: Age-associated SIRT2 expression changes; localization and substrate landscape review (URL: https://doi.org/10.3390/biology12121476; Nov 2023) (garmendiaberges2023ageassociatedchangesof pages 2-4).

Conclusion
Human SIRT2 is an NAD+-dependent lysine deacylase with dual deacetylase and defatty-acylase activities. Its cytosolic localization, nuclear shuttling, and stress-induced regulation allow SIRT2 to couple metabolic state and pathogen/stress signals to cytoskeletal control, membrane trafficking, and gene expression. Recent 2023–2024 advances highlight allosteric, substrate-selective SIRT2 modulators with broad-spectrum antiviral efficacy and proof-of-concept anti-inflammatory benefits in IBD models. Mechanistic precision—distinguishing deacetylase from defatty-acylase outputs—appears central to therapeutic potential and may explain divergences between pharmacologic and genetic perturbation outcomes (roche2023anallostericinhibitor pages 8-10, shenk2024drugstargetingsirtuin pages 8-9, hou2024sirt2inhibitionimproves pages 3-5, yang2024ahomogeneoustimeresolved pages 18-19).

References

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(wang2022golgistressinduces pages 4-6): Miao Wang, Yugang Zhang, Garrison P. Komaniecki, Xuan Lu, Ji Cao, Mingming Zhang, Tao Yu, Dan Hou, Nicole A. Spiegelman, Ming Yang, Ian R. Price, and Hening Lin. Golgi stress induces sirt2 to counteract shigella infection via defatty-acylation. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32227-x, doi:10.1038/s41467-022-32227-x. This article has 21 citations and is from a highest quality peer-reviewed journal.
(wang2022golgistressinduces pages 6-8): Miao Wang, Yugang Zhang, Garrison P. Komaniecki, Xuan Lu, Ji Cao, Mingming Zhang, Tao Yu, Dan Hou, Nicole A. Spiegelman, Ming Yang, Ian R. Price, and Hening Lin. Golgi stress induces sirt2 to counteract shigella infection via defatty-acylation. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32227-x, doi:10.1038/s41467-022-32227-x. This article has 21 citations and is from a highest quality peer-reviewed journal.
(wang2022golgistressinduces pages 2-4): Miao Wang, Yugang Zhang, Garrison P. Komaniecki, Xuan Lu, Ji Cao, Mingming Zhang, Tao Yu, Dan Hou, Nicole A. Spiegelman, Ming Yang, Ian R. Price, and Hening Lin. Golgi stress induces sirt2 to counteract shigella infection via defatty-acylation. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32227-x, doi:10.1038/s41467-022-32227-x. This article has 21 citations and is from a highest quality peer-reviewed journal.
(shenk2024drugstargetingsirtuin pages 19-21): Thomas Shenk, John L. Kulp III, and Lillian W. Chiang. Drugs targeting sirtuin 2 exhibit broad-spectrum anti-infective activity. Pharmaceuticals, 17:1298, Sep 2024. URL: https://doi.org/10.3390/ph17101298, doi:10.3390/ph17101298. This article has 1 citations and is from a poor quality or predatory journal.
(wang2022golgistressinduces pages 10-11): Miao Wang, Yugang Zhang, Garrison P. Komaniecki, Xuan Lu, Ji Cao, Mingming Zhang, Tao Yu, Dan Hou, Nicole A. Spiegelman, Ming Yang, Ian R. Price, and Hening Lin. Golgi stress induces sirt2 to counteract shigella infection via defatty-acylation. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32227-x, doi:10.1038/s41467-022-32227-x. This article has 21 citations and is from a highest quality peer-reviewed journal.

Citations

shenk2024drugstargetingsirtuin pages 6-8
shenk2024drugstargetingsirtuin pages 4-6
garmendiaberges2023ageassociatedchangesof pages 2-4
yang2024ahomogeneoustimeresolved pages 18-19
colcerasa2024structureactivitystudiesof pages 54-56
shenk2024drugstargetingsirtuin pages 8-9
roche2023anallostericinhibitor pages 3-5
roche2023anallostericinhibitor pages 8-10
shenk2024drugstargetingsirtuin pages 2-4
shenk2024drugstargetingsirtuin pages 11-12
roche2023anallostericinhibitor pages 2-3
roche2023anallostericinhibitor pages 1-2
wang2022golgistressinduces pages 4-6
wang2022golgistressinduces pages 6-8
wang2022golgistressinduces pages 2-4
shenk2024drugstargetingsirtuin pages 19-21
wang2022golgistressinduces pages 10-11
https://doi.org/10.3390/ph17101298;
https://doi.org/10.1371/journal.pone.0305000;
https://doi.org/10.1021/acs.jmedchem.4c00229;
https://doi.org/10.3390/biology12121476;
https://doi.org/10.1172/jci158978;
https://doi.org/10.1073/pnas.2319833121;
https://doi.org/10.1128/msystems.00510-23;
https://doi.org/10.1021/acs.jmedchem.4c00229
https://doi.org/10.3390/ph17101298
https://doi.org/10.1073/pnas.2319833121
https://doi.org/10.1371/journal.pone.0305000
https://doi.org/10.3390/biology12121476
https://doi.org/10.1038/s41467-022-32227-x;
https://doi.org/10.1038/s41467-022-32227-x
https://doi.org/10.1128/msystems.00510-23
https://doi.org/10.3390/biom14091160
https://doi.org/10.3390/biology12121476,
https://doi.org/10.3390/ph17101298,
https://doi.org/10.1371/journal.pone.0305000,
https://doi.org/10.1021/acs.jmedchem.4c00229,
https://doi.org/10.1172/jci158978,
https://doi.org/10.1073/pnas.2319833121,
https://doi.org/10.1128/msystems.00510-23,
https://doi.org/10.1038/s41467-022-32227-x,

📄 View Raw YAML

id: Q8IXJ6
gene_symbol: SIRT2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NAD-dependent protein deacetylase and defatty-acylase that 
  functions primarily in the cytoplasm but shuttles to the nucleus during G2/M 
  transition. SIRT2 deacetylates histones (H4K16, H3K18, H3K56), alpha-tubulin 
  (K40), and numerous non-histone substrates including transcription factors 
  (FOXO1, FOXO3, HIF1A, RELA/p65), metabolic enzymes (ACLY, G6PD, PCK1), and 
  cell cycle regulators (CDC20, BubR1). Also possesses efficient demyristoylase 
  and depalmitoylase activities. Key roles include regulation of cell cycle 
  progression, chromatin condensation during mitosis, metabolic regulation, and 
  peripheral nerve myelination.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SIRT2 localizes to the nucleus, particularly during G2/M transition
      and mitosis. North and Verdin (PMID:17726514) demonstrated that SIRT2 
      undergoes nucleo-cytoplasmic shuttling via CRM1-dependent nuclear export, 
      with nuclear accumulation during mitosis.
    action: ACCEPT
    reason: Well-supported by multiple experimental studies. SIRT2 shuttles 
      between cytoplasm and nucleus, with nuclear enrichment during mitosis 
      where it associates with chromatin and deacetylates H4K16.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: SIRT2 maintains a largely cytoplasmic localization during
        interphase by active nuclear export in a Crm1-dependent manner... During
        the cell cycle, SIRT2 becomes enriched in the nucleus
    - reference_id: PMID:23908241
      supporting_text: during infection with the bacterium Listeria 
        monocytogenes, the host deacetylase sirtuin 2 (SIRT2) translocates to 
        the nucleus
    - reference_id: file:human/SIRT2/SIRT2-deep-research-falcon.md
      supporting_text: See deep research file for comprehensive analysis
- term:
    id: GO:0017136
    label: histone deacetylase activity, NAD-dependent
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SIRT2 is a well-established NAD-dependent histone deacetylase. 
      Crystal structure (PMID:11427894) reveals NAD-binding domain and catalytic
      mechanism. Deacetylates H4K16 preferentially (PMID:16648462), as well as 
      H3K18 and H3K56.
    action: ACCEPT
    reason: Core molecular function of SIRT2 confirmed by structural and 
      biochemical studies. The NAD-dependent deacetylase activity is fundamental
      to all sirtuin functions.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Sir2 is an NAD-dependent histone deacetylase... The 1.7 A
        crystal structure of the 323 amino acid catalytic core of human SIRT2
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16 during mitosis
- term:
    id: GO:0000183
    label: rDNA heterochromatin formation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This annotation is based on yeast Sir2 function. While SIRT2 has 
      chromatin-related functions, direct evidence for human SIRT2 involvement 
      in rDNA heterochromatin formation is limited.
    action: KEEP_AS_NON_CORE
    reason: Inferred from yeast Sir2 function. Human SIRT2 is primarily 
      cytoplasmic and its chromatin functions are more related to mitotic H4K16 
      deacetylation than rDNA silencing. The IBA annotation may be conservative 
      but represents possible ancestral function.
- term:
    id: GO:0000781
    label: chromosome, telomeric region
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Automated annotation based on inter-ontology links. While yeast 
      Sir2 functions in telomeric silencing, direct evidence for human SIRT2 at 
      telomeres is limited.
    action: UNDECIDED
    reason: Lacks direct experimental evidence for human SIRT2. This may be 
      extrapolated from yeast Sir2 telomeric functions. SIRT2 does associate 
      with chromatin during mitosis but telomeric localization specifically is 
      not well documented.
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 has been implicated in immune responses, particularly through
      its role in NF-kB regulation (PMID:21081649) and bacterial infection 
      response (PMID:23908241).
    action: KEEP_AS_NON_CORE
    reason: While SIRT2 deacetylates p65/RELA and modulates NF-kB signaling, 
      this represents a downstream consequence of its deacetylase activity 
      rather than a core function. The term is also quite broad.
    supported_by:
    - reference_id: PMID:21081649
      supporting_text: SIRT2 interacts with p65 in the cytoplasm and 
        deacetylates p65 in vitro and in vivo at Lys310
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate of IBA annotation. Nuclear localization is well-supported
      experimentally.
    action: ACCEPT
    reason: Consistent with IBA annotation and experimental evidence showing 
      SIRT2 nuclear shuttling and enrichment during mitosis.
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SIRT2 associates with chromosomes during mitosis, where it 
      deacetylates H4K16 to promote chromatin condensation.
    action: ACCEPT
    reason: Supported by experimental evidence showing SIRT2 association with 
      mitotic chromatin and its role in H4K16 deacetylation during cell cycle.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16 during mitosis
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 is predominantly cytoplasmic during interphase, maintained by
      active CRM1-dependent nuclear export.
    action: ACCEPT
    reason: Well-established primary localization of SIRT2. Multiple studies 
      confirm cytoplasmic residence during interphase where it functions as 
      tubulin deacetylase.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: SIRT2 often appears distinctly localized in the 
        cytoplasm... SIRT2 was exclusively cytoplasmic in 99.5% of cells
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SIRT2 localizes to centrosomes during prophase, colocalizing with 
      Aurora A kinase.
    action: ACCEPT
    reason: Well-supported by immunofluorescence studies showing SIRT2 
      enrichment at centrosomes during early mitosis.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: During early prophase, endogenous SIRT2 became enriched 
        at the centrosome demonstrated by its colocalization with Aurora A
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SIRT2 localizes to centrioles during metaphase.
    action: ACCEPT
    reason: Experimentally supported localization during mitosis.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: At metaphase, SIRT2 remained concentrated in the 
        centrioles and spread along the spindle fibers
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SIRT2 localizes along spindle fibers during metaphase.
    action: ACCEPT
    reason: Well-documented localization pattern during mitosis, consistent with
      SIRT2's role in cell cycle regulation.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: At metaphase, SIRT2 remained concentrated in the 
        centrioles and spread along the spindle fibers
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SIRT2 associates with microtubule cytoskeleton as tubulin 
      deacetylase.
    action: ACCEPT
    reason: Consistent with SIRT2's well-established role as alpha-tubulin K40 
      deacetylase.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 associates with microtubules as the primary tubulin 
      deacetylase.
    action: ACCEPT
    reason: Core localization related to tubulin deacetylase function. SIRT2 
      deacetylates alpha-tubulin at K40.
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 regulates transcription through histone deacetylation and 
      deacetylation of transcription factors (FOXO, p65, HIF1A).
    action: KEEP_AS_NON_CORE
    reason: This is an indirect/downstream effect of SIRT2's deacetylase 
      activity on chromatin and transcription factors, not a direct 
      transcriptional function.
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 regulates autophagy through deacetylation of FOXO1 
      (PMID:20543840). Acetylated FOXO1 binds ATG7 to induce autophagy.
    action: KEEP_AS_NON_CORE
    reason: SIRT2 negatively regulates autophagy by deacetylating FOXO1. This is
      a documented but not core function.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: In response to stress, FoxO1 was acetylated by 
        dissociation from sirtuin-2 (SIRT2)... the acetylated FoxO1 bound to 
        Atg7
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 is involved in peripheral nerve myelination through 
      Par-3/aPKC signaling (PMID:21949390).
    action: KEEP_AS_NON_CORE
    reason: Documented role in Schwann cell myelination but this is a 
      tissue-specific function rather than a core molecular function.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sirt2 deacetylates Par-3, a master regulator of cell 
        polarity
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 has been reported to possess ADP-ribosyltransferase activity 
      (PMID:10381378).
    action: MARK_AS_OVER_ANNOTATED
    reason: While sirtuins can exhibit weak ADP-ribosyltransferase activity, 
      this is not considered a major physiological function of SIRT2. The term 
      is also very general and uninformative.
- term:
    id: GO:0017136
    label: histone deacetylase activity, NAD-dependent
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate annotation - core molecular function of SIRT2.
    action: ACCEPT
    reason: Fundamental enzymatic activity confirmed by structural and 
      biochemical studies.
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 has been implicated in differentiation of various cell types 
      including muscle (PMID:12887892), adipocytes, and oligodendrocytes.
    action: KEEP_AS_NON_CORE
    reason: Very broad term. SIRT2 affects differentiation through its 
      deacetylase activity on various substrates, but this is not a core 
      molecular function.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Localization based on UniProt subcellular location annotation.
    action: UNDECIDED
    reason: Limited direct experimental evidence for SIRT2 localization to 
      growth cones. May be inferred from neuronal expression and microtubule 
      association.
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 localizes to the midbody during cytokinesis, colocalizing 
      with Aurora B.
    action: ACCEPT
    reason: Well-documented localization during cytokinesis.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: during cytokinesis, SIRT2 associated with the midbody... 
        SIRT2 colocalized with Aurora B, a midbody-localized protein
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Core molecular function - SIRT2 deacetylates numerous protein 
      substrates including histones, tubulin, and transcription factors in an 
      NAD-dependent manner.
    action: ACCEPT
    reason: Fundamental enzymatic activity of SIRT2 supported by extensive 
      biochemical evidence.
- term:
    id: GO:0042995
    label: cell projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: General localization potentially related to microtubule association
      in neuronal projections.
    action: KEEP_AS_NON_CORE
    reason: Broad term that may be inferred from SIRT2's microtubule association
      and expression in neurons.
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: SIRT2 promotes proteasomal degradation of substrates like HIF1A by 
      deacetylating them, which increases their ubiquitination (PMID:24681946).
    action: KEEP_AS_NON_CORE
    reason: Indirect effect - SIRT2 deacetylates substrates, which can then be 
      ubiquitinated and degraded. This is a downstream consequence of 
      deacetylase activity.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: Deacetylation of HIF-1alpha by SIRT2 resulted in 
        increased binding affinity for prolyl hydroxylase 2... and increased 
        HIF-1alpha hydroxylation and ubiquitination
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Neuronal cell body localization based on expression in neurons.
    action: KEEP_AS_NON_CORE
    reason: Consistent with SIRT2 expression in neurons but represents 
      tissue-specific rather than core localization.
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 is highly expressed in myelin and functions in peripheral 
      myelination (PMID:21949390).
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization in Schwann cells related to myelination
      function.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sirt2 expression in SCs is correlated with that of 
        structural myelin components during both developmental myelination and 
        remyelination
- term:
    id: GO:0043687
    label: post-translational protein modification
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 performs deacetylation and defatty-acylation, both 
      post-translational modifications.
    action: ACCEPT
    reason: Accurate but very broad description of SIRT2's enzymatic function.
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 modulates innate immunity through NF-kB regulation and 
      response to bacterial infection (PMID:23908241).
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of deacetylase activity on immune signaling 
      pathways.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 contains a zinc-binding domain essential for structure and 
      function.
    action: MODIFY
    reason: Should be more specific - SIRT2 binds zinc ion, not general metal 
      ions.
    proposed_replacement_terms:
    - id: GO:0008270
      label: zinc ion binding
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: a smaller domain composed of a helical module and a 
        zinc-binding module
- term:
    id: GO:0046890
    label: regulation of lipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: SIRT2 regulates lipid biosynthesis by deacetylating and 
      destabilizing ACLY (PMID:23932781).
    action: KEEP_AS_NON_CORE
    reason: Documented role in lipid metabolism through ACLY regulation, but 
      this is a downstream metabolic consequence of deacetylase activity.
    supported_by:
    - reference_id: PMID:23932781
      supporting_text: the protein deacetylase sirtuin 2 (SIRT2) deacetylates 
        and destabilizes ACLY
- term:
    id: GO:0046970
    label: histone H4K16 deacetylase activity, NAD-dependent
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: SIRT2 preferentially deacetylates H4K16, particularly during 
      mitosis, promoting chromatin condensation (PMID:16648462).
    action: ACCEPT
    reason: Well-established specific substrate preference of SIRT2. H4K16 is 
      the preferred histone substrate.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16
- term:
    id: GO:0051093
    label: negative regulation of developmental process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Very broad term - SIRT2 affects various developmental processes 
      including muscle differentiation and adipogenesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad and vague. More specific terms should be used for SIRT2's 
      roles in specific developmental contexts.
- term:
    id: GO:0051239
    label: regulation of multicellular organismal process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Extremely broad term reflecting SIRT2's pleiotropic effects.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general to be informative. More specific process terms are 
      appropriate.
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: SIRT2 requires NAD+ as a cofactor for its 
      deacetylase/defatty-acylase activity.
    action: ACCEPT
    reason: Confirmed by crystal structure showing NAD-binding Rossmann fold 
      domain.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: reveals an NAD-binding domain, which is a variant of the 
        Rossmann fold
- term:
    id: GO:0051301
    label: cell division
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 regulates cell division through multiple mechanisms including
      chromatin condensation, spindle checkpoint, and cytokinesis.
    action: ACCEPT
    reason: Core biological process for SIRT2. Well-supported by localization 
      studies and functional analyses.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: SIRT2 contributes to the proper progression through 
        mitosis
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit
- term:
    id: GO:0051321
    label: meiotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: SIRT2 has been implicated in oocyte maturation and meiosis 
      regulation.
    action: KEEP_AS_NON_CORE
    reason: Evidence for meiotic roles exists but is less extensive than mitotic
      functions.
- term:
    id: GO:0062013
    label: positive regulation of small molecule metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Broad term reflecting SIRT2's metabolic regulatory functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general. More specific metabolic process terms are more 
      informative.
- term:
    id: GO:0070403
    label: NAD+ binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: SIRT2 binds NAD+ as essential cofactor for catalysis.
    action: ACCEPT
    reason: Core requirement for SIRT2 enzymatic activity confirmed 
      structurally.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Sir2 is an NAD-dependent histone deacetylase
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: SIRT2 regulates hypoxia response by deacetylating HIF1A, promoting 
      its hydroxylation and degradation (PMID:24681946).
    action: KEEP_AS_NON_CORE
    reason: Well-documented role through HIF1A regulation but represents 
      downstream effect of deacetylase activity.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2-mediated deacetylation of HIF-1alpha regulates its 
        stability in tumour cells
- term:
    id: GO:0140773
    label: NAD-dependent protein demyristoylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: SIRT2 possesses efficient demyristoylase activity with kcat/Km 
      higher than deacetylase activity (PMID:25704306).
    action: ACCEPT
    reason: Well-characterized enzymatic activity supported by kinetic and 
      structural studies.
    supported_by:
    - reference_id: PMID:25704306
      supporting_text: The catalytic efficiency (kcat/Km) for the removal of a 
        myristoyl group is slightly higher than that for the removal of an 
        acetyl group
- term:
    id: GO:0140774
    label: NAD-dependent protein depalmitoylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: SIRT2 can remove palmitoyl groups from lysine residues, though less
      efficiently than myristoyl groups.
    action: ACCEPT
    reason: Documented defatty-acylase activity, though myristoyl substrates are
      preferred.
    supported_by:
    - reference_id: PMID:25704306
      supporting_text: the defatty-acylase activity toward palmitoyl groups is 
        not efficient, which may result from the limited depth of the active 
        site
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12697818
  review:
    summary: General protein binding based on interaction with CDC14B and other 
      cell cycle regulators.
    action: MODIFY
    reason: Protein binding is uninformative. The referenced paper shows SIRT2 
      interacts with CDC14B phosphatase in context of mitotic regulation.
    proposed_replacement_terms:
    - id: GO:0019903
      label: protein phosphatase binding
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12887892
  review:
    summary: Interaction with MyoD transcription factor in context of muscle 
      differentiation.
    action: MODIFY
    reason: Should be more specific - SIRT2 binds transcription factors to 
      regulate their activity.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: Large-scale protein interaction mapping study.
    action: REMOVE
    reason: Generic protein binding annotation from high-throughput screen is 
      uninformative. More specific interaction terms should be used.
    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions
        by mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21081649
  review:
    summary: Interaction with p65/RELA subunit of NF-kB.
    action: MODIFY
    reason: Should be annotated with more specific term for transcription factor
      binding.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:21081649
      supporting_text: SIRT2 interacts with p65 in the cytoplasm and 
        deacetylates p65 in vitro and in vivo
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653829
  review:
    summary: Protein interactome study for autism-related pathways.
    action: REMOVE
    reason: Generic protein binding from interaction screen is uninformative.
    supported_by:
    - reference_id: PMID:21653829
      supporting_text: Protein interactome reveals converging molecular pathways
        among autism disorders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24769394
  review:
    summary: Interaction with G6PD (glucose-6-phosphate dehydrogenase).
    action: KEEP_AS_NON_CORE
    reason: Represents a specific substrate interaction. SIRT2 deacetylates G6PD
      to regulate pentose phosphate pathway.
    supported_by:
    - reference_id: PMID:24769394
      supporting_text: Regulation of G6PD acetylation by SIRT2 and KAT9 
        modulates NADPH homeostasis and cell survival during oxidative stress.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24825348
  review:
    summary: Interaction with BubR1 checkpoint kinase.
    action: MODIFY
    reason: Should use more specific term. SIRT2 deacetylates BubR1 in spindle 
      checkpoint.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
    supported_by:
    - reference_id: PMID:24825348
      supporting_text: SIRT2 induces the checkpoint kinase BubR1 to increase 
        lifespan.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: High-throughput proteome-scale interaction study.
    action: REMOVE
    reason: Generic protein binding from large-scale screen is uninformative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
        cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15213244
  review:
    summary: Interaction with HOXA10 homeobox transcription factor.
    action: MODIFY
    reason: Should be more specific - transcription factor binding.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:15213244
      supporting_text: Human histone deacetylase SIRT2 interacts with the 
        homeobox transcription factor HOXA10.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20543840
  review:
    summary: Interaction with FOXO1 transcription factor.
    action: MODIFY
    reason: SIRT2 binds and deacetylates FOXO1. Should be transcription factor 
      binding.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: FoxO1 was acetylated by dissociation from sirtuin-2 
        (SIRT2)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27512957
  review:
    summary: Interaction with BEX4 which inhibits SIRT2 tubulin deacetylase 
      activity.
    action: KEEP_AS_NON_CORE
    reason: Documents regulatory interaction but protein binding term is too 
      general.
    supported_by:
    - reference_id: PMID:27512957
      supporting_text: Oncogenic microtubule hyperacetylation through 
        BEX4-mediated sirtuin 2 inhibition.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24681946
  review:
    summary: Interaction with HIF1A.
    action: MODIFY
    reason: SIRT2 binds and deacetylates HIF1A transcription factor.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2 directly interacted with HIF-1alpha and 
        deacetylated Lys709 of HIF-1alpha
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18722353
  review:
    summary: Interaction with p300 acetyltransferase.
    action: MODIFY
    reason: SIRT2 is acetylated and regulated by p300. Should use histone 
      acetyltransferase binding.
    proposed_replacement_terms:
    - id: GO:0035035
      label: histone acetyltransferase binding
    supported_by:
    - reference_id: PMID:18722353
      supporting_text: p300 interacts with Sirt2... and triggers the acetylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21949390
  review:
    summary: Interaction with Par-3 polarity protein.
    action: KEEP_AS_NON_CORE
    reason: Specific substrate interaction in context of myelination.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sirt2 deacetylates Par-3, a master regulator of cell 
        polarity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23932781
  review:
    summary: Interaction with ACLY (ATP-citrate lyase).
    action: KEEP_AS_NON_CORE
    reason: Specific substrate interaction. SIRT2 deacetylates ACLY to regulate 
      lipid metabolism.
    supported_by:
    - reference_id: PMID:23932781
      supporting_text: the protein deacetylase sirtuin 2 (SIRT2) deacetylates 
        and destabilizes ACLY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17726514
  review:
    summary: Interaction with Aurora A and Aurora B kinases.
    action: MODIFY
    reason: SIRT2 interacts with Aurora kinases during mitosis. Should be 
      protein kinase binding.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: coimmunoprecipitation experiments with FLAG-tagged SIRT2 
        and Myc-tagged Aurora A indicate that these two proteins interact
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17172643
  review:
    summary: Interaction with CBP in context of pre-mRNA 3-end processing.
    action: MODIFY
    reason: CBP is a histone acetyltransferase. Should use more specific term.
    proposed_replacement_terms:
    - id: GO:0035035
      label: histone acetyltransferase binding
    supported_by:
    - reference_id: PMID:17172643
      supporting_text: 2006 Dec 17. Multiple histone deacetylases and the 
        CREB-binding protein regulate pre-mRNA 3'-end processing.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 represses transcription through histone deacetylation and 
      transcription factor modification.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect through substrate modification.
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: General HDAC activity - should be NAD-dependent specific term.
    action: MODIFY
    reason: SIRT2 is a class III NAD-dependent HDAC, not a Zn-dependent HDAC.
    proposed_replacement_terms:
    - id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 is primarily cytoplasmic, not mitochondrial.
    action: REMOVE
    reason: SIRT2 is the cytoplasmic sirtuin. SIRT3-5 are the mitochondrial 
      sirtuins. Any mitochondrial detection likely represents contamination.
- term:
    id: GO:0016042
    label: lipid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 affects lipid metabolism through multiple substrates.
    action: KEEP_AS_NON_CORE
    reason: Metabolic consequence of deacetylase activity.
- term:
    id: GO:0022011
    label: myelination in peripheral nervous system
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 regulates peripheral myelination.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function documented in mouse studies.
- term:
    id: GO:0031641
    label: regulation of myelination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 regulates myelination through Par-3/aPKC pathway.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein 
      catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 promotes substrate degradation through deacetylation.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect.
- term:
    id: GO:0033010
    label: paranodal junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 localization in myelin structures.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Broad deacetylase activity on non-histone substrates.
    action: ACCEPT
    reason: Core enzymatic function - SIRT2 deacetylates many protein 
      substrates.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 involved in oxidative stress response.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic effect through various substrates.
- term:
    id: GO:0040029
    label: epigenetic regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 affects gene expression through histone deacetylation.
    action: ACCEPT
    reason: Direct epigenetic function through H4K16 and H3K18 deacetylation.
- term:
    id: GO:0042903
    label: tubulin deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: SIRT2 is the primary tubulin deacetylase.
    action: ACCEPT
    reason: Core enzymatic function.
- term:
    id: GO:0043220
    label: Schmidt-Lanterman incisure
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 localization in myelin structures.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0045599
    label: negative regulation of fat cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 inhibits adipogenesis.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental function.
- term:
    id: GO:0045836
    label: positive regulation of meiotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 role in meiosis from ortholog data.
    action: KEEP_AS_NON_CORE
    reason: Less characterized than mitotic functions.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Context-dependent positive transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect - SIRT2 effects on transcription are 
      substrate-dependent.
- term:
    id: GO:0051781
    label: positive regulation of cell division
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 promotes proper cell division.
    action: ACCEPT
    reason: Consistent with cell cycle functions.
- term:
    id: GO:0051987
    label: positive regulation of attachment of spindle microtubules to 
      kinetochore
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 role in spindle checkpoint.
    action: KEEP_AS_NON_CORE
    reason: Related to cell cycle function.
- term:
    id: GO:0061433
    label: cellular response to caloric restriction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Sirtuins involved in metabolic adaptation.
    action: KEEP_AS_NON_CORE
    reason: General sirtuin function.
- term:
    id: GO:0071872
    label: cellular response to epinephrine stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 involved in hormonal metabolic responses.
    action: KEEP_AS_NON_CORE
    reason: Physiological context.
- term:
    id: GO:1900119
    label: positive regulation of execution phase of apoptosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 can promote apoptosis in certain contexts.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent effect.
- term:
    id: GO:1900195
    label: positive regulation of oocyte maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 role in oocyte maturation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function.
- term:
    id: GO:2000378
    label: negative regulation of reactive oxygen species metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SIRT2 affects ROS through multiple pathways.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nuclear localization confirmed by immunofluorescence in HPA/Cell 
      Atlas.
    action: ACCEPT
    reason: Consistent with SIRT2 nuclear shuttling and chromatin association.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Interestingly, SIRT2 appears to be excluded from nucleoli when 
      nuclear.
    action: REMOVE
    reason: Contradicts published data showing SIRT2 is excluded from nucleoli.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: Upon LMB treatment, SIRT2-FLAG was sequestered in the 
        nucleus but was excluded from the nucleoli
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Cytosolic localization confirmed by immunofluorescence.
    action: ACCEPT
    reason: Primary localization of SIRT2 during interphase.
- term:
    id: GO:0007084
    label: mitotic nuclear membrane reassembly
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2995410
  review:
    summary: SIRT2 involved in nuclear envelope reassembly pathway via ANKLE2 
      deacetylation.
    action: KEEP_AS_NON_CORE
    reason: Documented Reactome pathway but represents specific mitotic 
      function.
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9667952
  review:
    summary: SIRT2 deacetylates ANKLE2 in Reactome pathway.
    action: ACCEPT
    reason: Core enzymatic function in curated pathway.
- term:
    id: GO:0140219
    label: histone methacryllysine demethacrylase activity
  evidence_type: IDA
  original_reference_id: PMID:34961760
  review:
    summary: SIRT2 can remove methacryl modification from histone lysines.
    action: ACCEPT
    reason: Newly characterized enzymatic activity extending SIRT2's substrate 
      range.
    supported_by:
    - reference_id: PMID:34961760
      supporting_text: Histone lysine methacrylation is a dynamic 
        post-translational modification regulated by HAT1 and SIRT2.
- term:
    id: GO:0140228
    label: histone benzoyllysine debenzoylase activity
  evidence_type: IDA
  original_reference_id: PMID:30154464
  review:
    summary: SIRT2 regulates histone lysine benzoylation by removing benzoyl 
      groups.
    action: ACCEPT
    reason: Experimentally validated enzymatic activity.
    supported_by:
    - reference_id: PMID:30154464
      supporting_text: Lysine benzoylation is a histone mark regulated by SIRT2.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: Mitochondrial localization from high-throughput proteomics.
    action: REMOVE
    reason: SIRT2 is primarily cytoplasmic. Mitochondrial detection likely 
      reflects cytoplasmic contamination or non-specific association. SIRT3-5 
      are the established mitochondrial sirtuins.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
        mitochondrial proteome and its dynamics in cellular context.
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:23932781
  review:
    summary: Direct demonstration of NAD-dependent deacetylase activity on ACLY 
      substrate.
    action: ACCEPT
    reason: Core enzymatic function confirmed with specific substrate.
    supported_by:
    - reference_id: PMID:23932781
      supporting_text: the protein deacetylase sirtuin 2 (SIRT2) deacetylates 
        and destabilizes ACLY
- term:
    id: GO:1902725
    label: negative regulation of satellite cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Inferred from mouse Sirt2 function in muscle.
    action: KEEP_AS_NON_CORE
    reason: Supported by mouse studies but represents tissue-specific function.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein 
      catabolic process
  evidence_type: IMP
  original_reference_id: PMID:24681946
  review:
    summary: SIRT2 promotes HIF1A degradation by deacetylation leading to 
      ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of SIRT2 deacetylase activity on specific 
      substrates.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: Deacetylation of HIF-1alpha by SIRT2 resulted in... 
        increased HIF-1alpha hydroxylation and ubiquitination
- term:
    id: GO:0040029
    label: epigenetic regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23908241
  review:
    summary: SIRT2 H3K18 deacetylation affects gene expression during infection.
    action: ACCEPT
    reason: Direct epigenetic function through histone modification.
    supported_by:
    - reference_id: PMID:23908241
      supporting_text: SIRT2 associates with the transcription start site of a 
        subset of genes repressed during infection and deacetylates histone H3 
        on lysine 18
- term:
    id: GO:1990404
    label: NAD+-protein mono-ADP-ribosyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:17456799
  negated: true
  review:
    summary: This is a NOT annotation indicating SIRT2 does not have 
      NAD+-protein mono-ADP-ribosyltransferase activity per the cited review.
    action: ACCEPT
    reason: The GOA record uses a NOT qualifier for this activity; we accept the
      negated annotation as the current curation position for SIRT2.
    supported_by:
    - reference_id: PMID:17456799
      supporting_text: Apr 24. Sirtuin functions in health and disease.
- term:
    id: GO:0045723
    label: positive regulation of fatty acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:23932781
  review:
    summary: Counter-intuitive annotation - SIRT2 actually destabilizes ACLY and
      should inhibit fatty acid synthesis. This annotation appears to be an 
      error.
    action: REMOVE
    reason: SIRT2 deacetylates and destabilizes ACLY, which should NEGATIVELY 
      regulate fatty acid synthesis, not positively. The referenced paper states
      SIRT2 deacetylates and destabilizes ACLY - stabilization of ACLY promotes 
      lipid synthesis.
    supported_by:
    - reference_id: PMID:23932781
      supporting_text: the protein deacetylase sirtuin 2 (SIRT2) deacetylates 
        and destabilizes ACLY
- term:
    id: GO:0140773
    label: NAD-dependent protein demyristoylase activity
  evidence_type: IDA
  original_reference_id: PMID:25704306
  review:
    summary: Kinetic and structural characterization of SIRT2 demyristoylase 
      activity.
    action: ACCEPT
    reason: Core enzymatic function with higher catalytic efficiency than 
      deacetylation.
    supported_by:
    - reference_id: PMID:25704306
      supporting_text: The catalytic efficiency (kcat/Km) for the removal of a 
        myristoyl group is slightly higher than that for the removal of an 
        acetyl group
- term:
    id: GO:0140773
    label: NAD-dependent protein demyristoylase activity
  evidence_type: IDA
  original_reference_id: PMID:32103017
  review:
    summary: Demyristoylase activity demonstrated in cellular context.
    action: ACCEPT
    reason: Additional experimental support for demyristoylase activity.
    supported_by:
    - reference_id: PMID:32103017
      supporting_text: NMT1 and NMT2 are lysine myristoyltransferases regulating
        the ARF6 GTPase cycle.
- term:
    id: GO:0140774
    label: NAD-dependent protein depalmitoylase activity
  evidence_type: IDA
  original_reference_id: PMID:32103017
  review:
    summary: Depalmitoylase activity demonstrated experimentally.
    action: ACCEPT
    reason: Documented enzymatic activity though less efficient than 
      demyristoylation.
    supported_by:
    - reference_id: PMID:32103017
      supporting_text: NMT1 and NMT2 are lysine myristoyltransferases regulating
        the ARF6 GTPase cycle.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:12887892
  review:
    summary: SIRT2 interacts with MyoD transcription factor.
    action: ACCEPT
    reason: More specific than generic protein binding.
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:15126506
  review:
    summary: Referenced paper is about SIRT1/FOXO4 interaction, not SIRT2.
    action: REMOVE
    reason: Incorrect gene - this paper describes SIRT1, not SIRT2, interacting 
      with FOXO4.
    supported_by:
    - reference_id: PMID:15126506
      supporting_text: 2004 May 4. FOXO4 is acetylated upon peroxide stress and 
        deacetylated by the longevity protein hSir2(SIRT1).
- term:
    id: GO:0003950
    label: NAD+ poly-ADP-ribosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:10381378
  review:
    summary: Early study suggesting ADP-ribosyltransferase activity based on NAD
      labeling.
    action: REMOVE
    reason: The activity described was mono-ADP-ribosylation, not 
      poly-ADP-ribosylation. SIRT2 does not have poly-ADP-ribosyltransferase 
      activity. Annotation should be to GO:1990404 (NAD+-protein 
      mono-ADP-ribosyltransferase activity) instead.
    proposed_replacement_terms:
    - id: GO:1990404
      label: NAD+-protein mono-ADP-ribosyltransferase activity
    supported_by:
    - reference_id: PMID:10381378
      supporting_text: Recombinant E. coli cobB and human SIRT2 sirtuin proteins
        were able to cause radioactivity to be transferred from [32P]NAD to 
        bovine serum albumin
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9667952
  review:
    summary: Cytosolic SIRT2 in Reactome pathway.
    action: ACCEPT
    reason: Consistent with primary localization.
- term:
    id: GO:0042903
    label: tubulin deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:23886946
  review:
    summary: SIRT2 tubulin deacetylase activity demonstrated in mitotic spindle 
      context.
    action: ACCEPT
    reason: Well-established core function of SIRT2 on alpha-tubulin K40.
    supported_by:
    - reference_id: PMID:23886946
      supporting_text: Jul 25. Furry promotes acetylation of microtubules in the
        mitotic spindle by inhibition of SIRT2 tubulin deacetylase.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:24681946
  review:
    summary: SIRT2 negatively regulates HIF1A-dependent transcription by 
      destabilizing HIF1A.
    action: KEEP_AS_NON_CORE
    reason: Indirect transcriptional effect through substrate modification.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2 regulates tumour hypoxia response by promoting 
        HIF-1α hydroxylation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:24681946
  review:
    summary: Cytosolic SIRT2 deacetylates HIF1A.
    action: ACCEPT
    reason: Confirms cytosolic function.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2 regulates tumour hypoxia response by promoting 
        HIF-1α hydroxylation.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein 
      catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Conserved function from ortholog data.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of deacetylase activity.
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: IMP
  original_reference_id: PMID:24681946
  review:
    summary: NAD-dependent deacetylation of HIF1A demonstrated by mutant 
      analysis.
    action: ACCEPT
    reason: Core function confirmed.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2 regulates tumour hypoxia response by promoting 
        HIF-1α hydroxylation.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:24681946
  review:
    summary: SIRT2 modulates hypoxia response through HIF1A regulation.
    action: KEEP_AS_NON_CORE
    reason: Specific physiological context for SIRT2 function.
    supported_by:
    - reference_id: PMID:24681946
      supporting_text: SIRT2 regulates tumour hypoxia response by promoting 
        HIF-1α hydroxylation.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20543840
  review:
    summary: Cytoplasmic localization where SIRT2 deacetylates FOXO1.
    action: ACCEPT
    reason: Confirms cytoplasmic function.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: Cytosolic FoxO1 is essential for the induction of 
        autophagy and tumour suppressor activity.
- term:
    id: GO:0006476
    label: protein deacetylation
  evidence_type: IDA
  original_reference_id: PMID:20543840
  review:
    summary: SIRT2 deacetylates FOXO1 transcription factor.
    action: ACCEPT
    reason: Core biological process for SIRT2.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: Cytosolic FoxO1 is essential for the induction of 
        autophagy and tumour suppressor activity.
- term:
    id: GO:0010507
    label: negative regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:20543840
  review:
    summary: SIRT2 inhibits autophagy by deacetylating FOXO1.
    action: KEEP_AS_NON_CORE
    reason: Documented but not core function.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: FoxO1 was acetylated by dissociation from sirtuin-2 
        (SIRT2)... the acetylated FoxO1 bound to Atg7... to influence the 
        autophagic process
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:20543840
  review:
    summary: SIRT2 deacetylates FOXO1.
    action: ACCEPT
    reason: Confirms broad substrate specificity beyond histones.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: Cytosolic FoxO1 is essential for the induction of 
        autophagy and tumour suppressor activity.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 involved in oxidative stress response through multiple 
      substrates.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic effect through various substrates including FOXO 
      factors.
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:20543840
  review:
    summary: SIRT2 inhibits autophagy-mediated protein degradation.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect through autophagy regulation.
    supported_by:
    - reference_id: PMID:20543840
      supporting_text: Cytosolic FoxO1 is essential for the induction of 
        autophagy and tumour suppressor activity.
- term:
    id: GO:0043388
    label: positive regulation of DNA binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Inferred from ortholog - SIRT2 affects transcription factor DNA 
      binding.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect through deacetylation of transcription factors.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Context-dependent transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect - SIRT2 can both activate and repress transcription 
      depending on substrate.
- term:
    id: GO:0061433
    label: cellular response to caloric restriction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Sirtuins involved in metabolic adaptation to caloric restriction.
    action: KEEP_AS_NON_CORE
    reason: General sirtuin function but not uniquely characteristic of SIRT2.
- term:
    id: GO:1900119
    label: positive regulation of execution phase of apoptosis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 can promote apoptosis in certain contexts.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent effect, not core function.
- term:
    id: GO:2000378
    label: negative regulation of reactive oxygen species metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 affects ROS through multiple pathways including FOXO factors.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect through substrate modification.
- term:
    id: GO:0045836
    label: positive regulation of meiotic nuclear division
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 role in meiosis inferred from orthologs.
    action: KEEP_AS_NON_CORE
    reason: Less well-characterized than mitotic functions.
- term:
    id: GO:0051781
    label: positive regulation of cell division
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 promotes proper cell division.
    action: ACCEPT
    reason: Consistent with well-documented mitotic functions.
- term:
    id: GO:0051987
    label: positive regulation of attachment of spindle microtubules to 
      kinetochore
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 role in spindle checkpoint.
    action: KEEP_AS_NON_CORE
    reason: Related to cell cycle function but specific mechanism unclear.
- term:
    id: GO:1900195
    label: positive regulation of oocyte maturation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 role in oocyte maturation from ortholog data.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental function.
- term:
    id: GO:0006476
    label: protein deacetylation
  evidence_type: IDA
  original_reference_id: PMID:21949390
  review:
    summary: SIRT2 deacetylates Par-3 in Schwann cells.
    action: ACCEPT
    reason: Core biological process demonstrated with specific substrate.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sir-two-homolog 2 (Sirt2) modulates peripheral 
        myelination through polarity protein Par-3/atypical protein kinase C 
        (aPKC) signaling.
- term:
    id: GO:0010801
    label: negative regulation of peptidyl-threonine phosphorylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 affects phosphorylation through aPKC regulation in 
      myelination.
    action: KEEP_AS_NON_CORE
    reason: Specific to Schwann cell function.
- term:
    id: GO:0022011
    label: myelination in peripheral nervous system
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 regulates peripheral myelination through Par-3/aPKC.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function well-documented in mouse.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sirt2 deacetylates Par-3, a master regulator of cell 
        polarity
- term:
    id: GO:0031641
    label: regulation of myelination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 regulates Schwann cell myelination.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function.
- term:
    id: GO:0033010
    label: paranodal junction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 localization in myelin structures from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization in myelinating cells.
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:21949390
  review:
    summary: NAD-dependent deacetylation of Par-3.
    action: ACCEPT
    reason: Core enzymatic function.
    supported_by:
    - reference_id: PMID:21949390
      supporting_text: Sir-two-homolog 2 (Sirt2) modulates peripheral 
        myelination through polarity protein Par-3/atypical protein kinase C 
        (aPKC) signaling.
- term:
    id: GO:0043219
    label: lateral loop
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 localization in myelin structures.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0043220
    label: Schmidt-Lanterman incisure
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 localization in myelin structures.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IDA
  original_reference_id: PMID:23908241
  review:
    summary: SIRT2 associates with transcription start sites during bacterial 
      infection.
    action: ACCEPT
    reason: Demonstrated by ChIP showing SIRT2 at gene promoters.
    supported_by:
    - reference_id: PMID:23908241
      supporting_text: SIRT2 associates with the transcription start site of a 
        subset of genes repressed during infection
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23908241
  review:
    summary: SIRT2 translocates to nucleus during bacterial infection.
    action: ACCEPT
    reason: Demonstrates stimulus-induced nuclear translocation.
    supported_by:
    - reference_id: PMID:23908241
      supporting_text: the host deacetylase sirtuin 2 (SIRT2) translocates to 
        the nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23908241
  review:
    summary: SIRT2 is cytoplasmic under basal conditions.
    action: ACCEPT
    reason: Primary localization confirmed.
    supported_by:
    - reference_id: PMID:23908241
      supporting_text: A role for SIRT2-dependent histone H3K18 deacetylation in
        bacterial infection.
- term:
    id: GO:0016042
    label: lipid catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 affects lipid metabolism through ACLY and other substrates.
    action: KEEP_AS_NON_CORE
    reason: Metabolic consequence of deacetylase activity.
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IMP
  original_reference_id: PMID:23908241
  review:
    summary: SIRT2 deacetylase activity required for H3K18 deacetylation during 
      infection.
    action: ACCEPT
    reason: Confirms deacetylase function in physiological context.
    supported_by:
    - reference_id: PMID:23908241
      supporting_text: A role for SIRT2-dependent histone H3K18 deacetylation in
        bacterial infection.
- term:
    id: GO:0071872
    label: cellular response to epinephrine stimulus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 involved in metabolic responses to hormonal stimuli.
    action: KEEP_AS_NON_CORE
    reason: Physiological context for metabolic regulation.
- term:
    id: GO:0045599
    label: negative regulation of fat cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 inhibits adipocyte differentiation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental function.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:18722353
  review:
    summary: SIRT2 inhibits p53-dependent transcription when active.
    action: KEEP_AS_NON_CORE
    reason: Indirect transcriptional effect.
    supported_by:
    - reference_id: PMID:18722353
      supporting_text: the acetylation of Sirt2 by p300 relieves the inhibitory 
        effect of Sirt2 on the transcriptional activity of p53
- term:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:18722353
  review:
    summary: SIRT2 NAD-dependent deacetylase activity regulated by p300 
      acetylation.
    action: ACCEPT
    reason: Core function with regulatory mechanism characterized.
    supported_by:
    - reference_id: PMID:18722353
      supporting_text: Acetylation of Sirt2 by p300 attenuates its deacetylase 
        activity.
- term:
    id: GO:0042903
    label: tubulin deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:18722353
  review:
    summary: SIRT2 deacetylates tubulin.
    action: ACCEPT
    reason: Duplicate of well-supported core function.
    supported_by:
    - reference_id: PMID:18722353
      supporting_text: Acetylation of Sirt2 by p300 attenuates its deacetylase 
        activity.
- term:
    id: GO:0090042
    label: tubulin deacetylation
  evidence_type: IDA
  original_reference_id: PMID:18722353
  review:
    summary: SIRT2 deacetylates tubulin.
    action: ACCEPT
    reason: Core biological process for cytoplasmic SIRT2.
    supported_by:
    - reference_id: PMID:18722353
      supporting_text: Acetylation of Sirt2 by p300 attenuates its deacetylase 
        activity.
- term:
    id: GO:0000792
    label: heterochromatin
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 associates with heterochromatin, inferred from Sir2 function.
    action: KEEP_AS_NON_CORE
    reason: Chromatin association during mitosis is documented, but constitutive
      heterochromatin localization is less clear.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16648462
  review:
    summary: SIRT2 enters nucleus during mitosis for H4K16 deacetylation.
    action: ACCEPT
    reason: Cell cycle-dependent nuclear localization.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16 during mitosis.
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IDA
  original_reference_id: PMID:16648462
  review:
    summary: SIRT2 associates with chromosomes during mitosis.
    action: ACCEPT
    reason: Consistent with H4K16 deacetylation function during mitosis.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16 during mitosis.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16648462
  review:
    summary: Primary cytoplasmic localization during interphase.
    action: ACCEPT
    reason: Well-established localization pattern.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16 during mitosis.
- term:
    id: GO:0033270
    label: paranode region of axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 in myelin structures from mouse data.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Neuronal cell body localization.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 in myelin from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0044224
    label: juxtaparanode region of axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 in axonal structures from mouse data.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific localization.
- term:
    id: GO:0046970
    label: histone H4K16 deacetylase activity, NAD-dependent
  evidence_type: IDA
  original_reference_id: PMID:16648462
  review:
    summary: SIRT2 shows preference for H4K16 deacetylation during mitosis.
    action: ACCEPT
    reason: Specific substrate preference established by biochemical studies.
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: SirT2 is a histone deacetylase with preference for 
        histone H4 Lys 16
- term:
    id: GO:0070446
    label: negative regulation of oligodendrocyte progenitor proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: SIRT2 role in CNS myelination from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific function.
- term:
    id: GO:0090042
    label: tubulin deacetylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Conserved tubulin deacetylation function.
    action: ACCEPT
    reason: Core biological process for SIRT2.
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:17488717
  review:
    summary: SIRT2 histone deacetylase activity regulated by CDK1 
      phosphorylation.
    action: MODIFY
    reason: Should be the more specific NAD-dependent term since SIRT2 is a 
      class III HDAC.
    proposed_replacement_terms:
    - id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    supported_by:
    - reference_id: PMID:17488717
      supporting_text: 2007 May 8. Mitotic regulation of SIRT2 by 
        cyclin-dependent kinase 1-dependent phosphorylation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15213244
  review:
    summary: Nuclear SIRT2 interacts with HOXA10 transcription factor.
    action: ACCEPT
    reason: Confirms nuclear functions of SIRT2.
    supported_by:
    - reference_id: PMID:15213244
      supporting_text: Human histone deacetylase SIRT2 interacts with the 
        homeobox transcription factor HOXA10.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 accumulates in nucleus upon LMB treatment or during mitosis.
    action: ACCEPT
    reason: Key study on nuclear shuttling.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: Interphase nucleo-cytoplasmic shuttling and localization 
        of SIRT2 during mitosis.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15213244
  review:
    summary: Cytoplasmic localization observed.
    action: ACCEPT
    reason: Consistent with other studies.
    supported_by:
    - reference_id: PMID:15213244
      supporting_text: Human histone deacetylase SIRT2 interacts with the 
        homeobox transcription factor HOXA10.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 predominantly cytoplasmic during interphase due to active 
      nuclear export.
    action: ACCEPT
    reason: Key study characterizing SIRT2 localization dynamics.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: SIRT2 was exclusively cytoplasmic in 99.5% of cells
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:17488717
  review:
    summary: SIRT2 localizes to centrosome, phosphorylated by CDK1.
    action: ACCEPT
    reason: Mitotic localization confirmed.
    supported_by:
    - reference_id: PMID:17488717
      supporting_text: 2007 May 8. Mitotic regulation of SIRT2 by 
        cyclin-dependent kinase 1-dependent phosphorylation.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 enriched at centrosome during prophase.
    action: ACCEPT
    reason: Well-documented mitotic localization.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: During early prophase, endogenous SIRT2 became enriched 
        at the centrosome
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 concentrated at centrioles during metaphase.
    action: ACCEPT
    reason: Detailed mitotic localization study.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: Interphase nucleo-cytoplasmic shuttling and localization 
        of SIRT2 during mitosis.
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 spreads along spindle fibers during metaphase.
    action: ACCEPT
    reason: Consistent with tubulin deacetylase function.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: At metaphase, SIRT2 remained concentrated in the 
        centrioles and spread along the spindle fibers
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IDA
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 localizes to midbody during cytokinesis, colocalizing with 
      Aurora B.
    action: ACCEPT
    reason: Critical localization for cytokinesis function.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: during cytokinesis, SIRT2 associated with the midbody
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Perinuclear localization pattern.
    action: KEEP_AS_NON_CORE
    reason: May reflect centrosomal/MTOC association.
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IMP
  original_reference_id: PMID:17726514
  review:
    summary: SIRT2 overexpression affects mitotic progression and causes 
      multinucleation.
    action: ACCEPT
    reason: Core function of SIRT2 in cell cycle regulation.
    supported_by:
    - reference_id: PMID:17726514
      supporting_text: Overexpression of wild-type GFP-SIRT2 increased by 
        3-fold... the number of cells containing 2 or more nuclei, suggesting 
        that SIRT2 contributes to the proper progression through mitosis
- term:
    id: GO:0021762
    label: substantia nigra development
  evidence_type: HEP
  original_reference_id: PMID:22926577
  review:
    summary: SIRT2 detected in substantia nigra proteomics study comparing 
      neurodegenerative diseases.
    action: UNDECIDED
    reason: Expression-based annotation from disease study. Does not demonstrate
      direct role in substantia nigra development.
    supported_by:
    - reference_id: PMID:22926577
      supporting_text: 2012 Aug 28. Quantitative proteomic analysis of human 
        substantia nigra in Alzheimer's disease, Huntington's disease and 
        Multiple sclerosis.
- term:
    id: GO:0034983
    label: peptidyl-lysine deacetylation
  evidence_type: IDA
  original_reference_id: PMID:23932781
  review:
    summary: SIRT2 deacetylates ACLY at specific lysine residues.
    action: ACCEPT
    reason: Core biological process with specific substrate.
    supported_by:
    - reference_id: PMID:23932781
      supporting_text: 2013 Aug 8. Acetylation stabilizes ATP-citrate lyase to 
        promote lipid biosynthesis and tumor growth.
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21841822
  review:
    summary: SIRT2 deacetylates FOXO3, leading to its ubiquitination and 
      degradation.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect on protein stability through deacetylation.
    supported_by:
    - reference_id: PMID:21841822
      supporting_text: Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to 
        Skp2-mediated FOXO3 ubiquitination and degradation.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:11427894
  review:
    summary: Crystal structure reveals zinc-binding module essential for SIRT2 
      structure.
    action: ACCEPT
    reason: Structurally confirmed - zinc binding is required for proper 
      folding.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: a smaller domain composed of a helical module and a 
        zinc-binding module
- term:
    id: GO:0017136
    label: histone deacetylase activity, NAD-dependent
  evidence_type: IDA
  original_reference_id: PMID:11427894
  review:
    summary: Crystal structure and mutagenesis confirm NAD-dependent histone 
      deacetylase activity.
    action: ACCEPT
    reason: Foundational structural study establishing SIRT2 enzymatic 
      mechanism.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Structure of the histone deacetylase SIRT2.
- term:
    id: GO:0070403
    label: NAD+ binding
  evidence_type: IDA
  original_reference_id: PMID:11427894
  review:
    summary: NAD-binding domain structurally characterized in SIRT2.
    action: ACCEPT
    reason: Essential cofactor binding confirmed by crystal structure.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Structure of the histone deacetylase SIRT2.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16079181
  review:
    summary: Comparative study confirming SIRT2 cytoplasmic localization.
    action: ACCEPT
    reason: Systematic characterization of sirtuin localization.
    supported_by:
    - reference_id: PMID:16079181
      supporting_text: 2005 Aug 3. Evolutionarily conserved and nonconserved 
        cellular localizations and functions of human SIRT proteins.
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:17172643
  review:
    summary: Broad protein deacetylase activity demonstrated.
    action: ACCEPT
    reason: SIRT2 deacetylates many non-histone substrates, making this general 
      term appropriate.
    supported_by:
    - reference_id: PMID:17172643
      supporting_text: 2006 Dec 17. Multiple histone deacetylases and the 
        CREB-binding protein regulate pre-mRNA 3'-end processing.
- term:
    id: GO:0003950
    label: NAD+ poly-ADP-ribosyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:17456799
  negated: true
  review:
    summary: This is a NOT annotation indicating SIRT2 does not have NAD+ 
      poly-ADP- ribosyltransferase activity.
    action: ACCEPT
    reason: The GOA record uses a NOT qualifier for this activity; we accept the
      negated annotation.
    supported_by:
    - reference_id: PMID:17456799
      supporting_text: Apr 24. Sirtuin functions in health and disease.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:12697818
  review:
    summary: Cytoplasmic SIRT2 interacts with cell cycle regulators.
    action: ACCEPT
    reason: Functional cytoplasmic localization.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IDA
  original_reference_id: PMID:12620231
  review:
    summary: SIRT2 associates with microtubules as tubulin deacetylase.
    action: ACCEPT
    reason: Foundational study on SIRT2-microtubule association.
    supported_by:
    - reference_id: PMID:12620231
      supporting_text: The human Sir2 ortholog, SIRT2, is an NAD+-dependent 
        tubulin deacetylase.
- term:
    id: GO:0007096
    label: regulation of exit from mitosis
  evidence_type: NAS
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 regulates mitotic exit through CDC14B interaction.
    action: ACCEPT
    reason: Core cell cycle function of SIRT2.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0017136
    label: histone deacetylase activity, NAD-dependent
  evidence_type: IDA
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 histone deacetylase activity in context of cell cycle 
      regulation.
    action: ACCEPT
    reason: Core function confirmed with cellular substrates.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0035035
    label: histone acetyltransferase binding
  evidence_type: IPI
  original_reference_id: PMID:12887892
  review:
    summary: SIRT2 interacts with PCAF acetyltransferase.
    action: ACCEPT
    reason: Documented regulatory interaction with opposing enzyme.
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0042325
    label: regulation of phosphorylation
  evidence_type: NAS
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 affects phosphorylation through phosphatase interactions.
    action: KEEP_AS_NON_CORE
    reason: Indirect effect through CDC14B interaction.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0042826
    label: histone deacetylase binding
  evidence_type: IPI
  original_reference_id: PMID:12620231
  review:
    summary: SIRT2 interacts with HDAC6 in tubulin deacetylation complex.
    action: ACCEPT
    reason: Documented interaction with class II HDAC.
    supported_by:
    - reference_id: PMID:12620231
      supporting_text: The human Sir2 ortholog, SIRT2, is an NAD+-dependent 
        tubulin deacetylase.
- term:
    id: GO:0042903
    label: tubulin deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:12620231
  review:
    summary: Original demonstration of SIRT2 tubulin deacetylase activity.
    action: ACCEPT
    reason: Foundational paper establishing SIRT2 as major tubulin deacetylase.
    supported_by:
    - reference_id: PMID:12620231
      supporting_text: The human Sir2 ortholog, SIRT2, is an NAD+-dependent 
        tubulin deacetylase.
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 interacts with polyubiquitinated proteins.
    action: KEEP_AS_NON_CORE
    reason: Documented but functional significance unclear.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0045843
    label: negative regulation of striated muscle tissue development
  evidence_type: IDA
  original_reference_id: PMID:12887892
  review:
    summary: SIRT2 inhibits muscle differentiation through MyoD deacetylation.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:12887892
  review:
    summary: SIRT2 represses MyoD-dependent transcription.
    action: KEEP_AS_NON_CORE
    reason: Indirect transcriptional effect through substrate deacetylation.
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0051775
    label: response to redox state
  evidence_type: NAS
  original_reference_id: PMID:12887892
  review:
    summary: SIRT2 activity influenced by cellular NAD+/NADH ratio.
    action: ACCEPT
    reason: NAD-dependent activity inherently links SIRT2 to cellular redox 
      state.
    supported_by:
    - reference_id: PMID:12887892
      supporting_text: Sir2 regulates skeletal muscle differentiation as a 
        potential sensor of the redox state.
- term:
    id: GO:0000183
    label: rDNA heterochromatin formation
  evidence_type: NAS
  original_reference_id: PMID:11427894
  review:
    summary: Extrapolated from yeast Sir2 function mentioned in structural 
      paper.
    action: KEEP_AS_NON_CORE
    reason: Based on yeast homolog function. Human SIRT2 is primarily 
      cytoplasmic.
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Structure of the histone deacetylase SIRT2.
- term:
    id: GO:0031507
    label: heterochromatin formation
  evidence_type: NAS
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 role in heterochromatin from H4K16 deacetylation.
    action: KEEP_AS_NON_CORE
    reason: Related to chromatin function but primary role is during mitosis.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: Role for human SIRT2 NAD-dependent deacetylase activity 
        in control of mitotic exit in the cell cycle.
- term:
    id: GO:0031509
    label: subtelomeric heterochromatin formation
  evidence_type: NAS
  original_reference_id: PMID:11427894
  review:
    summary: Extrapolated from yeast Sir2 telomeric silencing function.
    action: UNDECIDED
    reason: Limited direct evidence for human SIRT2 in telomeric silencing.
# NEW annotations for core functions not yet in GOA
    supported_by:
    - reference_id: PMID:11427894
      supporting_text: Structure of the histone deacetylase SIRT2.
- term:
    id: GO:0031115
    label: negative regulation of microtubule polymerization
  evidence_type: IDA
  original_reference_id: PMID:23886946
  review:
    summary: SIRT2 deacetylates alpha-tubulin at K40, which destabilizes 
      microtubules.
    action: NEW
    reason: Direct consequence of SIRT2 tubulin deacetylase activity - 
      deacetylation promotes microtubule depolymerization.
    supported_by:
    - reference_id: PMID:23886946
      supporting_text: AGK2, a specific inhibitor of SIRT2, increased the level 
        of MT acetylation in the mitotic spindle, indicating that SIRT2 is 
        involved in the deacetylation of spindle MTs
- term:
    id: GO:0016192
    label: vesicle-mediated transport
  evidence_type: IMP
  original_reference_id: PMID:32103017
  review:
    summary: SIRT2 demyristoylates ARF6 to regulate vesicle trafficking.
    action: NEW
    reason: Demyristoylation of ARF6 by SIRT2 affects membrane trafficking and 
      vesicle formation.
    supported_by:
    - reference_id: PMID:32103017
      supporting_text: We demonstrate that the NAD+-dependent deacylase SIRT2 
        removes the myristoyl group
- term:
    id: GO:0030261
    label: chromosome condensation
  evidence_type: IMP
  original_reference_id: PMID:12697818
  review:
    summary: SIRT2 deacetylates H4K16 during G2/M transition for chromosome 
      condensation.
    action: NEW
    reason: H4K16 deacetylation by SIRT2 is required for proper chromosome 
      condensation during mitosis.
    supported_by:
    - reference_id: PMID:12697818
      supporting_text: The SIRT2 protein is a NAD-dependent deacetylase (NDAC), 
        the abundance of which increases dramatically during mitosis and is 
        multiply phosphorylated at the G(2)/M transition of the cell cycle
- term:
    id: GO:0073163
    label: E-cadherin localization to cell surface
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:25704306
      supporting_text: The catalytic efficiency (kcat/Km) for the removal of a 
        myristoyl group is slightly higher than that for the removal of an 
        acetyl group
    - reference_id: doi:10.1073/pnas.2319833121
      supporting_text: Sirt2 inhibition shifts ARF6 dynamics to increase 
        E-cadherin at the cell surface and improve epithelial barrier function
- term:
    id: GO:0042742
    label: defense response to bacterium
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: doi:10.1038/s41467-022-32227-x
      supporting_text: Golgi stress induces SIRT2 to counteract Shigella 
        infection via defatty-acylation; SIRT2 removes lysine fatty acylations 
        installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family
        members and CHMP5
    - reference_id: doi:10.1172/jci158978
      supporting_text: FLS-359 allosteric SIRT2 inhibitor exhibits 
        broad-spectrum antiviral activity
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: doi:10.1038/s41467-022-32227-x
      supporting_text: Golgi stress induces SIRT2 to counteract Shigella 
        infection via defatty-acylation; SIRT2 removes lysine fatty acylations 
        installed by bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family
        members and CHMP5
    - reference_id: doi:10.1172/jci158978
      supporting_text: FLS-359 allosteric SIRT2 inhibitor exhibits 
        broad-spectrum antiviral activity
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10381378
  title: Characterization of five human cDNAs with homology to the yeast SIR2 
    gene
  full_text_unavailable: true
  findings:
  - statement: SIRT2 identified as one of five human sirtuins
    supporting_text: Here five human sirtuin cDNAs are characterized. The SIRT1 
      sequence has the closest homology to the S. cerevisiae Sir2p.
    reference_section_type: ABSTRACT
  - statement: Demonstrated weak ADP-ribosyltransferase activity
    supporting_text: Recombinant E. coli cobB and human SIRT2 sirtuin proteins 
      were able to cause radioactivity to be transferred from [32P]NAD to bovine
      serum albumin (BSA).
    reference_section_type: ABSTRACT
- id: PMID:11427894
  title: Structure of the histone deacetylase SIRT2
  full_text_unavailable: true
  findings:
  - statement: Crystal structure at 1.7A resolution
    supporting_text: The 1.7 A crystal structure of the 323 amino acid catalytic
      core of human SIRT2, a homolog of yeast Sir2, reveals an NAD-binding 
      domain, which is a variant of the Rossmann fold, and a smaller domain 
      composed of a helical module and a zinc-binding module.
    reference_section_type: ABSTRACT
  - statement: NAD-binding Rossmann fold domain identified
    supporting_text: The 1.7 A crystal structure of the 323 amino acid catalytic
      core of human SIRT2, a homolog of yeast Sir2, reveals an NAD-binding 
      domain, which is a variant of the Rossmann fold
    reference_section_type: ABSTRACT
  - statement: Zinc-binding module essential for structure
    supporting_text: a smaller domain composed of a helical module and a 
      zinc-binding module
    reference_section_type: ABSTRACT
- id: PMID:12620231
  title: The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin 
    deacetylase.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates alpha-tubulin at K40
    supporting_text: SIRT2 deacetylates lysine-40 of alpha-tubulin both in vitro
      and in vivo.
    reference_section_type: ABSTRACT
  - statement: Functions with HDAC6 in tubulin deacetylation
    supporting_text: SIRT2 colocalizes and interacts in vivo with HDAC6, another
      tubulin deacetylase.
    reference_section_type: ABSTRACT
- id: PMID:12697818
  title: Role for human SIRT2 NAD-dependent deacetylase activity in control of 
    mitotic exit
  full_text_unavailable: true
  findings:
  - statement: SIRT2 regulates mitotic exit
    supporting_text: Our functional studies of human SIRT2, a homolog of the 
      product of the yeast SIR2 gene, indicate that it plays a role in mitosis.
    reference_section_type: ABSTRACT
  - statement: Interacts with CDC14B phosphatase
    supporting_text: Overexpression of the protein phosphatase CDC14B, but not 
      its close homolog CDC14A, results in dephosphorylation of SIRT2 with a 
      subsequent decrease in the abundance of SIRT2 protein.
    reference_section_type: ABSTRACT
- id: PMID:12887892
  title: Sir2 regulates skeletal muscle differentiation
  full_text_unavailable: true
  findings:
  - statement: SIRT2 inhibits MyoD-dependent muscle differentiation
    supporting_text: Sir2 forms a complex with the acetyltransferase PCAF and 
      MyoD and, when overexpressed, retards muscle differentiation.
    reference_section_type: ABSTRACT
  - statement: Interacts with PCAF acetyltransferase
    supporting_text: Sir2 forms a complex with the acetyltransferase PCAF and 
      MyoD
    reference_section_type: ABSTRACT
- id: PMID:16648462
  title: SirT2 is a histone deacetylase with preference for histone H4 Lys 16 
    during mitosis
  full_text_unavailable: true
  findings:
  - statement: H4K16 is preferred histone substrate
    supporting_text: SirT2 and its yeast counterpart Hst2 have a strong 
      preference for histone H4K16Ac in their deacetylation activity in vitro 
      and in vivo.
    reference_section_type: ABSTRACT
  - statement: Nuclear during mitosis for chromatin condensation
    supporting_text: We have pinpointed the decrease in global levels of H4K16Ac
      during the mammalian cell cycle to the G2/M transition that coincides with
      SirT2 localization on chromatin.
    reference_section_type: ABSTRACT
- id: PMID:17488717
  title: Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent 
    phosphorylation.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 phosphorylated at Ser368 by CDK1
    supporting_text: SIRT2 is phosphorylated both in vitro and in vivo on serine
      368 by the cell-cycle regulator, cyclin-dependent kinase 1
    reference_section_type: ABSTRACT
  - statement: Dephosphorylated by CDC14A/B
    supporting_text: dephosphorylated by the phosphatases CDC14A and CDC14B
    reference_section_type: ABSTRACT
- id: PMID:17726514
  title: Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 
    during mitosis
  full_text_unavailable: false
  findings:
  - statement: CRM1-dependent nuclear export
    supporting_text: These results indicate that SIRT2 is actively exported from
      the nucleus in a Crm1-dependent manner.
    reference_section_type: RESULTS
  - statement: Localizes to centrosome, spindle, midbody during mitosis
    supporting_text: During early prophase, endogenous SIRT2 became enriched at 
      the centrosome demonstrated by its colocalization with Aurora A, a mitotic
      regulatory kinase also found on the centrosomes
    reference_section_type: RESULTS
  - statement: Interacts with Aurora A and Aurora B
    supporting_text: Utilizying coimmunoprecipitation experiments with 
      FLAG-tagged SIRT2 and Myc-tagged Aurora A indicate that these two proteins
      interact in a mutliprotein complex
    reference_section_type: RESULTS
- id: PMID:18722353
  title: Acetylation of Sirt2 by p300 attenuates its deacetylase activity
  full_text_unavailable: true
  findings:
  - statement: p300 acetylates and inhibits SIRT2
    supporting_text: p300 interacts with Sirt2, a member of the Sir2 family, and
      triggers the acetylation and subsequent down-regulation of the 
      deacetylation activity of Sirt2
    reference_section_type: ABSTRACT
  - statement: Affects p53-dependent transcription
    supporting_text: the acetylation of Sirt2 by p300 relieves the inhibitory 
      effect of Sirt2 on the transcriptional activity of p53
    reference_section_type: ABSTRACT
- id: PMID:20543840
  title: Cytosolic FoxO1 is essential for the induction of autophagy and tumour 
    suppressor activity.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates FOXO1
    supporting_text: FoxO1 was acetylated by dissociation from sirtuin-2 
      (SIRT2), a NAD(+)-dependent histone deacetylase
    reference_section_type: ABSTRACT
  - statement: Regulates autophagy through FOXO1-ATG7 interaction
    supporting_text: the acetylated FoxO1 bound to Atg7, an E1-like protein, to 
      influence the autophagic process leading to cell death
    reference_section_type: ABSTRACT
- id: PMID:21081649
  title: SIRT2 regulates NF-κB dependent gene expression through deacetylation 
    of p65 Lys310.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates p65 at K310
    supporting_text: SIRT2 interacts with p65 in the cytoplasm and deacetylates 
      p65 in vitro and in vivo at Lys310.
    reference_section_type: ABSTRACT
  - statement: Regulates NF-kB-dependent gene expression
    supporting_text: p65 is deacetylated by SIRT2 in the cytoplasm to regulate 
      the expression of specific NF-κB-dependent genes.
    reference_section_type: ABSTRACT
- id: PMID:21949390
  title: Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through 
    polarity protein Par-3/atypical protein kinase C (aPKC) signaling.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates Par-3
    supporting_text: Sirt2 deacetylates Par-3, a master regulator of cell 
      polarity
    reference_section_type: ABSTRACT
  - statement: Regulates Schwann cell polarity and myelination
    supporting_text: The deacetylation of Par-3 by Sirt2 decreases the activity 
      of the polarity complex signaling component aPKC, thereby regulating 
      myelin formation.
    reference_section_type: ABSTRACT
- id: PMID:23908241
  title: A role for SIRT2-dependent histone H3K18 deacetylation in bacterial 
    infection.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 translocates to nucleus during Listeria infection
    supporting_text: during infection with the bacterium Listeria monocytogenes,
      the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus, in a 
      manner dependent on the bacterial factor InlB
    reference_section_type: ABSTRACT
  - statement: Deacetylates H3K18 at gene promoters
    supporting_text: SIRT2 associates with the transcription start site of a 
      subset of genes repressed during infection and deacetylates histone H3 on 
      lysine 18 (H3K18)
    reference_section_type: ABSTRACT
- id: PMID:23932781
  title: Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis 
    and tumor growth.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates ACLY at K540/546/554
    supporting_text: ACLY is acetylated at lysine residues 540, 546, and 554 
      (3K)
    reference_section_type: ABSTRACT
  - statement: Destabilizes ACLY by promoting ubiquitination
    supporting_text: the protein deacetylase sirtuin 2 (SIRT2) deacetylates and 
      destabilizes ACLY
    reference_section_type: ABSTRACT
- id: PMID:24681946
  title: SIRT2 regulates tumour hypoxia response by promoting HIF-1α 
    hydroxylation.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates HIF1A at K709
    supporting_text: SIRT2 directly interacted with HIF-1α and deacetylated 
      Lys709 of HIF-1α
    reference_section_type: ABSTRACT
  - statement: Promotes HIF1A hydroxylation and degradation
    supporting_text: Deacetylation of HIF-1α by SIRT2 resulted in increased 
      binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α 
      stability, and increased HIF-1α hydroxylation and ubiquitination.
    reference_section_type: ABSTRACT
- id: PMID:25704306
  title: Efficient demyristoylase activity of SIRT2
  full_text_unavailable: false
  findings:
  - statement: kcat/Km for demyristoylation higher than deacetylation
    supporting_text: The catalytic efficiency (kcat/Km) for the removal of a 
      myristoyl group is slightly higher than that for the removal of an acetyl 
      group.
    reference_section_type: ABSTRACT
  - statement: Crystal structure with thiomyristoyl peptide
    supporting_text: The crystal structure of SIRT2 in complex with a 
      thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic 
      pocket that can accommodate the myristoyl group.
    reference_section_type: ABSTRACT
  - statement: Large hydrophobic pocket accommodates fatty acyl groups
    supporting_text: The thiomyristoyl group of BHJH-TM1 is accommodated by a 
      hydrophobic pocket formed by several hydrophobic residues of SIRT2, 
      including Ile93, Phe96, Phe119, Phe131, Leu134, Leu138, Phe143, Ile169, 
      Phe190, Ile232, and Phe234
    reference_section_type: RESULTS
- id: PMID:32103017
  title: NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 
    GTPase cycle.
  full_text_unavailable: false
  findings:
  - statement: SIRT2 removes myristoyl and palmitoyl groups from lysines
    supporting_text: We demonstrate that the NAD+-dependent deacylase SIRT2 
      removes the myristoyl group
    reference_section_type: ABSTRACT
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass 
    spectrometry
  findings: []
- id: PMID:21653829
  title: Protein interactome reveals converging molecular pathways among autism 
    disorders.
  findings: []
- id: PMID:24769394
  title: Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH 
    homeostasis and cell survival during oxidative stress.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 deacetylates G6PD at lysine 403 in response to oxidative 
      stress to activate the pentose phosphate pathway
    supporting_text: cells sense extracellular oxidative stimuli to decrease 
      G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated 
      deacetylation and activation of G6PD stimulates PPP to supply cytosolic 
      NADPH to counteract oxidative damage
    reference_section_type: ABSTRACT
  - statement: K403 acetylation of G6PD prevents active dimer formation 
      resulting in complete loss of enzymatic activity
    supporting_text: The K403 acetylated G6PD is incapable of forming active 
      dimers and displays a complete loss of activity.
    reference_section_type: ABSTRACT
- id: PMID:24825348
  title: SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 maintains BubR1 levels by deacetylating lysine-668, 
      counteracting CBP acetyltransferase
    supporting_text: Here, we show that the loss of BubR1 levels with age is due
      to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of 
      BubR1 in a deacetylated state, which is counteracted by the 
      acetyltransferase CBP
    reference_section_type: ABSTRACT
  - statement: NAD(+) precursor NMN treatment increases BubR1 abundance in vivo 
      through SIRT2
    supporting_text: Overexpression of SIRT2 or treatment of mice with the 
      NAD(+) precursor nicotinamide mononucleotide (NMN) increases BubR1 
      abundance in vivo
    reference_section_type: ABSTRACT
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome.
  findings: []
- id: PMID:15213244
  title: Human histone deacetylase SIRT2 interacts with the homeobox 
    transcription factor HOXA10.
  full_text_unavailable: true
  findings:
  - statement: SIRT2 interacts with HOXA10 as identified by two-hybrid screen 
      and confirmed by co-immunoprecipitation
    supporting_text: Here we show for the first time that SIRT2 interacts with 
      the homeobox transcription factor, HOXA10, which was identified in a 
      two-hybrid screen. Interactions were confirmed by co-immunoprecipitation 
      from in vitro translations as well as in human cell-free extracts.
    reference_section_type: ABSTRACT
  - statement: SIRT2 interaction with HOXA10 suggests a role in mammalian 
      development
    supporting_text: Taken together with mouse knockout studies, our results 
      raise the intriguing possibility that SIRT2 plays a role in mammalian 
      development.
    reference_section_type: ABSTRACT
- id: PMID:27512957
  title: Oncogenic microtubule hyperacetylation through BEX4-mediated sirtuin 2 
    inhibition.
  full_text_unavailable: false
  findings:
  - statement: BEX4 interacts with alpha-tubulin and SIRT2 to inhibit 
      SIRT2-mediated tubulin deacetylation
    supporting_text: Among BEX proteins, BEX4 localizes to microtubules and 
      spindle poles, and interacts with α-tubulin (α-TUB) and sirtuin 2 (SIRT2).
      The overexpression of BEX4 leads to the hyperacetylation of α-TUB by 
      inhibiting SIRT2-mediated deacetylation.
    reference_section_type: ABSTRACT
  - statement: SIRT2 wild-type but not H187Y deacetylase-dead mutant forms 
      complex with BEX4
    supporting_text: A subsequent pull-down assay showed that SIRT2 wild-type, 
      but not the H187Y deacetylase activity dead mutant, formed a complex with 
      BEX4, whereas both SIRT2 wild-type and H187Y mutants interact with α-TUB
    reference_section_type: RESULTS
  - statement: BEX4 competes with SIRT2 for alpha-tubulin binding through its 
      middle domain
    supporting_text: Pull-down assays revealed that α-TUB bound to GST-BEX4 C 
      and very weakly to GST-BEX4 M. Interestingly, GST-BEX4 M only formed a 
      complex with SIRT2
    reference_section_type: RESULTS
- id: PMID:17172643
  title: Multiple histone deacetylases and the CREB-binding protein regulate 
    pre-mRNA 3-end processing.
  findings: []
- id: Reactome:R-HSA-2995410
  title: 'Reactome pathway: Mitotic nuclear membrane reassembly'
  findings: []
- id: Reactome:R-HSA-9667952
  title: 'Reactome pathway: SIRT2 deacetylates ANKLE2'
  findings: []
- id: PMID:34961760
  title: Histone lysine methacrylation is a dynamic post-translational 
    modification regulated by HAT1 and SIRT2.
  findings: []
- id: PMID:30154464
  title: Lysine benzoylation is a histone mark regulated by SIRT2.
  full_text_unavailable: false
  findings:
  - statement: SIRT2 is the only HDAC family member that removes histone lysine 
      benzoylation (Kbz) both in vitro and in vivo
    supporting_text: we demonstrate that SIRT2, a NAD+-dependent protein 
      deacetylase, removes histone Kbz both in vitro and in vivo
    reference_section_type: ABSTRACT
  - statement: SIRT2 has debenzoylase activity with Kcat/Km approximately 1/6 of
      deacetylase activity
    supporting_text: Kcat/Km for debenzoylation was approximately 1/6 of that 
      for deacetylation
    reference_section_type: RESULTS
  - statement: Loss of SIRT2 increases global histone Kbz levels especially on 
      H3 and H2B
    supporting_text: By examining core histone Kbz levels in Sirt2+/+ (wild-type
      (WT)) and Sirt2−/− (knockout (KO)) mouse embryonic fibroblast (MEF) cells,
      we found that loss of SIRT2 expression was associated with increased Kbz 
      levels, especially on H3 and H2B proteins
    reference_section_type: RESULTS
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its 
    dynamics in cellular context.
  findings: []
- id: PMID:17456799
  title: Sirtuin functions in health and disease.
  findings: []
- id: PMID:15126506
  title: FOXO4 is acetylated upon peroxide stress and deacetylated by the 
    longevity protein hSir2(SIRT1).
  findings: []
- id: PMID:23886946
  title: Furry promotes acetylation of microtubules in the mitotic spindle by 
    inhibition of SIRT2 tubulin deacetylase.
  findings: []
- id: PMID:22926577
  title: Quantitative proteomic analysis of human substantia nigra in 
    Alzheimer's disease, Huntington's disease and Multiple sclerosis.
  findings: []
- id: PMID:21841822
  title: Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 
    ubiquitination and degradation.
  findings: []
- id: PMID:16079181
  title: Evolutionarily conserved and nonconserved cellular localizations and 
    functions of human SIRT proteins.
  findings: []
- id: file:human/SIRT2/SIRT2-deep-research-falcon.md
  title: Deep research on SIRT2 function
  findings: []
core_functions:
- description: Deacetylates alpha-tubulin at K40 in cytoplasm, regulating 
    microtubule stability and dynamics
  molecular_function:
    id: GO:0042903
    label: tubulin deacetylase activity
  directly_involved_in:
  - id: GO:0031115
    label: negative regulation of microtubule polymerization
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005874
    label: microtubule
  substrates:
  - id: UniProtKB:Q71U36
    label: TUBA1A (alpha-tubulin)
  supported_by:
  - reference_id: PMID:11427894
    supporting_text: The 1.7 A crystal structure of the 323 amino acid catalytic
      core of human SIRT2
  - reference_id: PMID:23886946
    supporting_text: SIRT2 tubulin deacetylase activity demonstrated in mitotic 
      spindle context
- description: Demyristoylates ARF6 at K3, regulating membrane trafficking and 
    E-cadherin recycling to plasma membrane
  molecular_function:
    id: GO:0140773
    label: NAD-dependent protein demyristoylase activity
  directly_involved_in:
  - id: GO:0016192
    label: vesicle-mediated transport
  - id: GO:0073163
    label: E-cadherin localization to cell surface
  locations:
  - id: GO:0005829
    label: cytosol
  substrates:
  - id: UniProtKB:P62330
    label: ARF6 (ADP-ribosylation factor 6)
  supported_by:
  - reference_id: PMID:25704306
    supporting_text: The catalytic efficiency (kcat/Km) for the removal of a 
      myristoyl group is slightly higher than that for the removal of an acetyl 
      group
  - reference_id: doi:10.1073/pnas.2319833121
    supporting_text: Sirt2 inhibition shifts ARF6 dynamics to increase 
      E-cadherin at the cell surface and improve epithelial barrier function
- description: Deacetylates histone H4K16 during mitosis, promoting chromatin 
    condensation for proper chromosome segregation
  molecular_function:
    id: GO:0046970
    label: histone H4K16 deacetylase activity, NAD-dependent
  directly_involved_in:
  - id: GO:0030261
    label: chromosome condensation
  - id: GO:0051301
    label: cell division
  locations:
  - id: GO:0005694
    label: chromosome
  - id: GO:0005634
    label: nucleus
  substrates:
  - id: UniProtKB:P62805
    label: H4 histone
  supported_by:
  - reference_id: PMID:16648462
    supporting_text: SirT2 is a histone deacetylase with preference for histone 
      H4 Lys 16 during mitosis
  - reference_id: PMID:17726514
    supporting_text: SIRT2 contributes to the proper progression through 
      mitosis... During the cell cycle, SIRT2 becomes enriched in the nucleus
- description: Removes lysine fatty-acyl modifications installed by bacterial 
    effectors, counteracting pathogen virulence mechanisms
  molecular_function:
    id: GO:0140773
    label: NAD-dependent protein demyristoylase activity
  directly_involved_in:
  - id: GO:0042742
    label: defense response to bacterium
  - id: GO:0051607
    label: defense response to virus
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: doi:10.1038/s41467-022-32227-x
    supporting_text: Golgi stress induces SIRT2 to counteract Shigella infection
      via defatty-acylation; SIRT2 removes lysine fatty acylations installed by 
      bacterial effectors (e.g., Shigella IcsB) on Ras/Rho family members and 
      CHMP5
  - reference_id: doi:10.1172/jci158978
    supporting_text: FLS-359 allosteric SIRT2 inhibitor exhibits broad-spectrum 
      antiviral activity
proposed_new_terms: []
suggested_questions:
- question: What is the relative physiological importance of SIRT2's deacetylase
    versus defatty-acylase activities?
- question: What are the key physiological substrates for SIRT2 demyristoylase 
    activity?
- question: How is SIRT2 nuclear translocation regulated during the cell cycle 
    and stress responses?
suggested_experiments:
- description: Proteomics to identify SIRT2 demyristoylation substrates in cells
- description: Live-cell imaging to characterize SIRT2 localization dynamics 
    during cell cycle
- description: Structure-function studies to separate deacetylase and 
    defatty-acylase activities

SIRT2

Gene Description

Existing Annotations Review

Core Functions

Deacetylates alpha-tubulin at K40 in cytoplasm, regulating microtubule stability and dynamics

Demyristoylates ARF6 at K3, regulating membrane trafficking and E-cadherin recycling to plasma membrane

Deacetylates histone H4K16 during mitosis, promoting chromatin condensation for proper chromosome segregation

Removes lysine fatty-acyl modifications installed by bacterial effectors, counteracting pathogen virulence mechanisms

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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