OpenScientist hypothesis investigation - SIRT2 defense response to virus
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Blinded function-assignment run on the seed "SIRT2 has defense response to virus (GO:0051607)". It refuted the term as an unqualified assignment and found the direction of effect to be virus-specific and predominantly pro-viral.
"Direction is VIRUS-SPECIFIC, and the preponderance of decisive perturbation evidence points to SIRT2 acting as a host DEPENDENCY (pro-viral) factor"
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The two studies reading out infectious progeny, the metric that settles the sign, both show SIRT2 is required by the virus rather than restricting it.
"Both decisive infectious-progeny studies point pro-viral."
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The run concluded a single unqualified defense-response-to-virus annotation is not warranted for human SIRT2.
"the primary literature does not support a uniform host-restriction role"
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Antiviral phenotypes reported for individual viruses are downstream consequences of the deacetylase activity, not a separate host-defense function, which is why the term was withdrawn rather than retained as non-core.
"The antiviral phenotypes are **downstream, context-dependent consequences** of this deacetylase activity, not a distinct "defense response to virus" function."
Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic assignment of GO terms using logical inference
Automatic Gene Ontology annotation based on Rhea mapping
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity.
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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."
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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)."
Structure of the histone deacetylase SIRT2
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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."
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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"
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Zinc-binding module essential for structure
"a smaller domain composed of a helical module and a zinc-binding module"
The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
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SIRT2 deacetylates alpha-tubulin at K40
"SIRT2 deacetylates lysine-40 of alpha-tubulin both in vitro and in vivo."
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Functions with HDAC6 in tubulin deacetylation
"SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase."
Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
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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."
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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."
Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
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SIRT2 inhibits MyoD-dependent muscle differentiation
"Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation."
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Interacts with PCAF acetyltransferase
"Sir2 forms a complex with the acetyltransferase PCAF and MyoD"
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
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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."
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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."
Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation.
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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"
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Dephosphorylated by CDC14A/B
"dephosphorylated by the phosphatases CDC14A and CDC14B"
Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis
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CRM1-dependent nuclear export
"These results indicate that SIRT2 is actively exported from the nucleus in a Crm1-dependent manner."
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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"
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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"
Acetylation of Sirt2 by p300 attenuates its deacetylase activity
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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"
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Affects p53-dependent transcription
"the acetylation of Sirt2 by p300 relieves the inhibitory effect of Sirt2 on the transcriptional activity of p53"
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.
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SIRT2 deacetylates FOXO1
"FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD(+)-dependent histone deacetylase"
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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"
SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310.
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SIRT2 deacetylates p65 at K310
"SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo at Lys310."
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Regulates NF-kB-dependent gene expression
"p65 is deacetylated by SIRT2 in the cytoplasm to regulate the expression of specific NF-κB-dependent genes."
Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.
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SIRT2 deacetylates Par-3
"Sirt2 deacetylates Par-3, a master regulator of cell polarity"
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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."
A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection.
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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"
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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)"
Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.
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SIRT2 deacetylates ACLY at K540/546/554
"ACLY is acetylated at lysine residues 540, 546, and 554 (3K)"
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Destabilizes ACLY by promoting ubiquitination
"the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY"
SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
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SIRT2 deacetylates HIF1A at K709
"SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α"
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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."
Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies.
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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."
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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."
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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"
Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.
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High-resolution human Sirt2 structures resolve the NAD+/cofactor pocket, zinc-binding domain and catalytic active site
"Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism."
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Two-domain sirtuin architecture with Rossmann fold and zinc-binding domain separated by the active-site groove
"the two-domain structure typical for sirtuins-a larger domain with a Rossmann fold and a smaller zinc-binding domain that are separated through a large groove that constitutes the active site"
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A/B-pockets bind ADP-ribose moiety and C-pocket binds the nicotinamide of NAD+
"The A- and B-pocket, respectively, bind the ADPR moiety, whereas the C-pocket binds the NCA of NAD+. NAD+ is able to adopt different conformations"
NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.
Large-scale mapping of human protein-protein interactions by mass spectrometry
Protein interactome reveals converging molecular pathways among autism disorders.
Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.
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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"
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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."
SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.
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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"
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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"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10.
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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."
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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."
Oncogenic microtubule hyperacetylation through BEX4-mediated sirtuin 2 inhibition.
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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."
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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"
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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"
Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3-end processing.
Reactome pathway: Mitotic nuclear membrane reassembly
Reactome pathway: SIRT2 deacetylates ANKLE2
Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.
Lysine benzoylation is a histone mark regulated by SIRT2.
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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"
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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"
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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"
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Sirtuin functions in health and disease.
FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).
Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase.
Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.
Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.
Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.
Deep research on SIRT2 function
Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis
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Sirt2 inhibition protects the gut epithelial barrier by inhibiting Arf6-mediated endocytosis of E-cadherin
"the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6-mediated endocytosis of E-cadherin"