Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: HDAC6 is predominantly cytoplasmic, where it associates with microtubules and carries out its primary deacetylase functions on tubulin, HSP90, and cortactin [PMID:12024216]. The SE14 repeat region mediates cytoplasmic retention. Reason: Core localization. HDAC6 is established as a predominantly cytoplasmic deacetylase, distinct from nuclear HDACs. This is supported by extensive experimental evidence [PMID:12024216, UniProt Q9UBN7]. Supporting Evidence: PMID:12024216 HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules file:human/HDAC6/HDAC6-deep-research-falcon.md model: Edison Scientific Literature
GO:0019213 deacetylase activity	IBA GO_REF:0000033	ACCEPT	Summary: HDAC6 is a Zn2+-dependent deacetylase with two catalytic domains. It deacetylates non-histone substrates including alpha-tubulin, HSP90, cortactin, peroxiredoxins, and other proteins. Reason: Core molecular function. HDAC6 is a bona fide protein deacetylase. The term is appropriately general as a parent term to more specific deacetylase activities. Supporting Evidence: PMID:12024216 HDAC6, functions as a tubulin deacetylase
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: HDAC6 localizes to the cytosol where it carries out its deacetylase functions. Reason: Core localization. Cytosol is an appropriate more specific term than cytoplasm. HDAC6 is found in the soluble cytosolic fraction as well as associated with microtubules. Supporting Evidence: PMID:12024216 HDAC6 is localized exclusively in the cytoplasm
GO:0090042 tubulin deacetylation	IBA GO_REF:0000033	ACCEPT	Summary: HDAC6 deacetylates alpha-tubulin at K40, regulating microtubule stability and dynamics. This is one of the primary functions of HDAC6 [PMID:12024216]. Reason: Core biological process. Tubulin deacetylation is one of the best-characterized and most important functions of HDAC6. Multiple studies demonstrate this activity both in vitro and in vivo. Supporting Evidence: PMID:12024216 In vivo, the overexpression of HDAC6 leads to a global deacetylation of alpha-tubulin, whereas a decrease in HDAC6 increases alpha-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates alpha-tubulin in assembled microtubules.
GO:1904115 axon cytoplasm	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: HDAC6 localizes to axons and regulates axonal transport via tubulin deacetylation. Reason: While HDAC6 does localize to axons (by sequence similarity), this is a specialized neuronal localization rather than a core function across all cell types. Its axonal role relates to regulating microtubule dynamics and transport.
GO:0000118 histone deacetylase complex	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: HDAC6 can interact with other HDACs (e.g., HDAC11) but primarily functions as a cytoplasmic non-histone deacetylase, not as part of classical histone deacetylase complexes. Reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone substrates. While it can interact with other HDACs, it does not primarily function in canonical nuclear histone deacetylase complexes. This annotation may be misleading about HDAC6's actual role.
GO:0003779 actin binding	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: HDAC6 interacts with cortactin (an actin-binding protein) and F-actin. It deacetylates cortactin to regulate actin dynamics. Reason: HDAC6 does interact with actin cytoskeleton components, but the primary functional relationship is through cortactin deacetylation rather than direct actin binding as a core function.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: HDAC6 can shuttle to the nucleus under certain conditions (valine deprivation, DNA damage, differentiation) but is predominantly cytoplasmic. Reason: While HDAC6 can translocate to the nucleus, its primary localization and function is cytoplasmic. Nuclear localization is context-dependent and represents a specialized rather than core localization. Supporting Evidence: UniProt:Q9UBN7 Can shuttle between the cytoplasm and the nucleus (PubMed:39567688). Retained in the cytoplasm by binding to valine via the primate-specific SE14 repeat region
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate annotation for cytoplasm localization. Reason: Core localization. Same as IBA annotation - HDAC6 is predominantly cytoplasmic.
GO:0005813 centrosome	IEA GO_REF:0000044	ACCEPT	Summary: HDAC6 localizes to the centrosome where it participates in cilium disassembly. Reason: Core localization for cilium-related function. HDAC6 localizes to the centrosome/ ciliary basal body and is required for cilium disassembly via deacetylation of alpha-tubulin [PMID:17604723, PMID:26246421]. Supporting Evidence: PMID:17604723 interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: HDAC6 associates with the cytoskeleton, particularly microtubules. Reason: Core localization. HDAC6 associates with microtubules and the cytoskeleton as part of its role in regulating microtubule dynamics. Supporting Evidence: PMID:12024216 HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules
GO:0005929 cilium	IEA GO_REF:0000044	ACCEPT	Summary: HDAC6 localizes to cilia where it promotes ciliary disassembly via tubulin deacetylation. Reason: HDAC6 localizes to cilia/ciliary basal body and has a direct role in cilium disassembly through deacetylation of alpha-tubulin [PMID:17604723]. Supporting Evidence: PMID:17604723 Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly
GO:0006325 chromatin organization	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Despite being named a histone deacetylase, HDAC6 primarily functions on non-histone substrates in the cytoplasm. Reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone substrates. Its role in chromatin organization is minimal compared to nuclear HDACs. UniProt explicitly notes it was "originally thought to be a histone deacetylase" but subsequent work showed it primarily deacetylates non-histone substrates.
GO:0006914 autophagy	IEA GO_REF:0000043	ACCEPT	Summary: HDAC6 plays a genuine role in autophagy, particularly aggrephagy. It binds polyubiquitinated misfolded proteins via its ZnF-UBP domain and transports them to aggresomes for autophagic clearance [PMID:14675537, PMID:16192271]. Reason: Core function. HDAC6's role in autophagy/aggrephagy is well-established and represents a key non-deacetylase function mediated by its ZnF-UBP domain and dynein binding. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes PMID:16192271 HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation
GO:0006950 response to stress	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HDAC6 participates in cellular stress responses, particularly misfolded protein stress and heat stress responses. Reason: HDAC6 does participate in stress responses (misfolded protein stress, heat shock response), but this is a very broad term. The specific mechanisms (aggresome formation, HSP90 regulation) are more informative annotations.
GO:0008270 zinc ion binding	IEA GO_REF:0000120	ACCEPT	Summary: HDAC6 is a Zn2+-dependent deacetylase that binds 3 Zn2+ ions per subunit. Reason: Core molecular function. Zinc binding is essential for HDAC6's deacetylase activity and for the ZnF-UBP domain function. Supporting Evidence: UniProt:Q9UBN7 Binds 3 Zn(2+) ions per subunit
GO:0016236 macroautophagy	IEA GO_REF:0000117	ACCEPT	Summary: HDAC6 regulates macroautophagy through multiple mechanisms including aggresome formation and cortactin deacetylation promoting autophagosome-lysosome fusion. Reason: Core function. HDAC6's role in autophagy is well-established through its aggresome function and regulation of autophagosome-lysosome fusion. Supporting Evidence: PMID:16192271 HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin
GO:0016740 transferase activity	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: HDAC6 has E3 ubiquitin-protein ligase activity (transferase activity transferring ubiquitin), in addition to its deacetylase function. Reason: While HDAC6 does have ubiquitin ligase activity (mediates ubiquitination of MSH2), this is a more specialized function. The term is very broad and the more specific ubiquitin protein ligase activity term is more informative.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: HDAC6 is a hydrolase that cleaves acetyl groups from lysine residues. Reason: Core molecular function. Deacetylation is a hydrolysis reaction, so this parent term is accurate though very general.
GO:0030424 axon	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: HDAC6 localizes to axons where it regulates microtubule dynamics and axonal transport. Reason: Specialized neuronal localization. While HDAC6 is present in axons, this is cell-type specific rather than a core localization across all cell types.
GO:0030425 dendrite	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: HDAC6 localizes to dendrites in neurons. Reason: Specialized neuronal localization rather than core localization.
GO:0032886 regulation of microtubule-based process	IEA GO_REF:0000117	ACCEPT	Summary: HDAC6 regulates microtubule-based processes through deacetylation of alpha-tubulin, affecting microtubule stability, dynamics, and dependent processes. Reason: Core function. This accurately captures HDAC6's role in regulating microtubule dynamics through tubulin deacetylation. Supporting Evidence: PMID:12024216 overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility
GO:0043204 perikaryon	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: HDAC6 localizes to the perikaryon (cell body) of neurons. Reason: Specialized neuronal localization rather than core localization across all cell types.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: HDAC6 binds zinc ions which are required for its deacetylase activity. Reason: Core molecular function. Metal (zinc) binding is essential for HDAC6 catalytic activity.
GO:0051129 negative regulation of cellular component organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HDAC6 can negatively regulate cellular component organization through effects on microtubule stability and cilium disassembly. Reason: Very broad term. The specific effects (microtubule dynamics, cilium disassembly) are more informative annotations.
GO:0051130 positive regulation of cellular component organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HDAC6 can positively regulate cellular component organization through aggresome formation. Reason: Very broad term. More specific terms like aggresome assembly are more informative.
GO:0098732 macromolecule deacylation	IEA GO_REF:0000117	ACCEPT	Summary: HDAC6 catalyzes deacetylation (a type of deacylation) of proteins. Reason: Core function. Deacetylation is the primary enzymatic activity of HDAC6.
GO:0120025 plasma membrane bounded cell projection	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HDAC6 localizes to cell projections including cilia, axons, and dendrites. Reason: Very broad parent term. More specific terms (cilium, axon, dendrite) are more informative.
GO:0005515 protein binding	IPI PMID:12024216 HDAC6 is a microtubule-associated deacetylase.	MODIFY	Summary: Generic protein binding annotation from the study that identified HDAC6 as a tubulin deacetylase. Reason: 'Protein binding' is uninformative. This study showed HDAC6 binds tubulin, which should be captured by more specific terms like alpha-tubulin binding or microtubule binding. Proposed replacements: alpha-tubulin binding Supporting Evidence: PMID:12024216 HDAC6 is a microtubule-associated deacetylase.
GO:0005515 protein binding	IPI PMID:12354939 Histone deacetylase 6 binds polyubiquitin through its zinc f...	MODIFY	Summary: This study showed HDAC6 binds polyubiquitin through its zinc finger (PAZ/BUZ) domain. Reason: 'Protein binding' is uninformative. This study demonstrated ubiquitin binding which is captured by GO:0043130 (ubiquitin binding). Proposed replacements: ubiquitin binding Supporting Evidence: PMID:12354939 Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes.
GO:0005515 protein binding	IPI PMID:16919237 Breast cancer metastasis suppressor 1 (BRMS1) is stabilized ...	MODIFY	Summary: Study showing HDAC6 interaction (via HSP90 pathway). Reason: 'Protein binding' is uninformative. Should be captured by more specific binding terms. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:16919237 Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone.
GO:0005515 protein binding	IPI PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	MODIFY	Summary: Study showing HDAC6 interactions with beta-catenin and EGFR pathway components. Reason: 'Protein binding' is uninformative. More specific terms available. Proposed replacements: beta-catenin binding Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0005515 protein binding	IPI PMID:19036992 Direct binding with histone deacetylase 6 mediates the rever...	KEEP AS NON CORE	Summary: Study showing direct binding of HDAC6 with parkin at the centrosome. Reason: While 'protein binding' is uninformative, the parkin interaction relates to HDAC6's role in the autophagy/mitophagy pathway. Supporting Evidence: PMID:19036992 Direct binding with histone deacetylase 6 mediates the reversible recruitment of parkin to the centrosome.
GO:0005515 protein binding	IPI PMID:19167333 A centrosomal Cdc20-APC pathway controls dendrite morphogene...	KEEP AS NON CORE	Summary: Study on centrosomal Cdc20-APC pathway in dendrite morphogenesis. Reason: Interaction related to neuronal development, not core HDAC6 function. Supporting Evidence: PMID:19167333 A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons.
GO:0005515 protein binding	IPI PMID:19893491 CYLD negatively regulates cell-cycle progression by inactiva...	KEEP AS NON CORE	Summary: Study showing CYLD negatively regulates HDAC6 and tubulin acetylation. Reason: CYLD-HDAC6 interaction is a regulatory mechanism, not a core function. Supporting Evidence: PMID:19893491 CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.
GO:0005515 protein binding	IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b...	KEEP AS NON CORE	Summary: Study on HDAC6 regulation of EGFR trafficking. Reason: EGFR interaction may be indirect through HDAC6's effects on microtubule dynamics. Supporting Evidence: PMID:20029029 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
GO:0005515 protein binding	IPI PMID:21220424 Regulation of Tat acetylation and transactivation activity b...	KEEP AS NON CORE	Summary: Study on HDAC6 regulation of HIV Tat acetylation. Reason: Viral protein interaction, specialized context. Supporting Evidence: PMID:21220424 2011 Jan 10. Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6.
GO:0005515 protein binding	IPI PMID:21532619 The HTLV-1 Tax protein inhibits formation of stress granules...	KEEP AS NON CORE	Summary: Study showing HTLV-1 Tax protein interacts with HDAC6. Reason: Viral protein interaction, specialized context. Supporting Evidence: PMID:21532619 The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6.
GO:0005515 protein binding	IPI PMID:21847094 Class IIb HDAC6 regulates endothelial cell migration and ang...	MODIFY	Summary: Study showing HDAC6 deacetylates cortactin affecting angiogenesis. Reason: 'Protein binding' is uninformative. Cortactin is a known HDAC6 substrate. Proposed replacements: actin binding Supporting Evidence: PMID:21847094 Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.
GO:0005515 protein binding	IPI PMID:21952047 PKC alpha regulates Sendai virus-mediated interferon inducti...	KEEP AS NON CORE	Summary: Study on PKC alpha regulation of interferon induction via HDAC6. Reason: Signaling pathway interaction, downstream effect. Supporting Evidence: PMID:21952047 PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin.
GO:0005515 protein binding	IPI PMID:22193721 A novel GRK2/HDAC6 interaction modulates cell spreading and ...	KEEP AS NON CORE	Summary: Study showing GRK2/HDAC6 interaction modulates cell spreading and motility. Reason: Regulatory interaction affecting cell motility. Supporting Evidence: PMID:22193721 A novel GRK2/HDAC6 interaction modulates cell spreading and motility.
GO:0005515 protein binding	IPI PMID:22645275 Identification of novel ATP13A2 interactors and their role i...	KEEP AS NON CORE	Summary: Study on ATP13A2 interactors including HDAC6 in alpha-synuclein misfolding. Reason: Interaction relevant to protein quality control pathway. Supporting Evidence: PMID:22645275 May 29. Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity.
GO:0005515 protein binding	IPI PMID:23084749 Regulation of CD133 by HDAC6 promotes β-catenin signaling to...	KEEP AS NON CORE	Summary: Study on HDAC6 regulation of CD133 and beta-catenin signaling. Reason: Cancer signaling context, downstream effect. Supporting Evidence: PMID:23084749 2012 Oct 19. Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation.
GO:0005515 protein binding	IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ...	KEEP AS NON CORE	Summary: Mammalian membrane two-hybrid assay identifying protein interactions. Reason: High-throughput interaction data, context unclear. Supporting Evidence: PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells.
GO:0005515 protein binding	IPI PMID:29281743 HDAC6 controls innate immune and autophagy responses to TLR-...	KEEP AS NON CORE	Summary: Study on HDAC6 in innate immune and autophagy responses to Listeria infection. Reason: Infection context, relates to autophagy function. Supporting Evidence: PMID:29281743 eCollection 2017 Dec.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	KEEP AS NON CORE	Summary: Large-scale interactome study in EGFR network. Reason: High-throughput data, not specific to core function. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Interactome mapping of neurodegenerative disease proteins. Reason: High-throughput data related to protein aggregation. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Dual proteome-scale interactome study. Reason: High-throughput data, not specific to core function. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0000153 cytoplasmic ubiquitin ligase complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 has E3 ubiquitin ligase activity and can ubiquitinate substrates like MSH2. Reason: While HDAC6 has ubiquitin ligase activity, this is not its primary function. The deacetylase activity is the core function.
GO:0004407 histone deacetylase activity	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: HDAC6 was originally named for histone deacetylase activity but primarily deacetylates non-histone cytoplasmic substrates. Reason: UniProt explicitly notes that HDAC6 "was originally thought to be a histone deacetylase. However, subsequent work has shown that it is predominantly cytoplasmic and deacetylates a range of non-histone substrates." The more appropriate term is protein lysine deacetylase activity. Proposed replacements: protein lysine deacetylase activity
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate cytosol annotation. Reason: Core localization, consistent with other cytosol annotations.
GO:0008017 microtubule binding	IEA GO_REF:0000107	ACCEPT	Summary: HDAC6 associates with microtubules where it deacetylates alpha-tubulin. Reason: Core molecular function. HDAC6 binds microtubules as part of its tubulin deacetylase function [PMID:12024216]. Supporting Evidence: PMID:12024216 HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules
GO:0015630 microtubule cytoskeleton	IEA GO_REF:0000120	ACCEPT	Summary: HDAC6 localizes to the microtubule cytoskeleton. Reason: Core localization. HDAC6 associates with microtubules [PMID:12024216].
GO:0031648 protein destabilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 can promote protein destabilization through deacetylation and ubiquitination. Reason: Downstream effect of HDAC6 activity on specific substrates (e.g., MSH2).
GO:0032461 positive regulation of protein oligomerization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 can affect protein oligomerization through its deacetylase activity. Reason: Downstream effect, context-specific (e.g., tau aggregation).
GO:0032991 protein-containing complex	IEA GO_REF:0000107	ACCEPT	Summary: Very generic term indicating HDAC6 is part of protein complexes. Reason: True but very general. HDAC6 participates in multiple protein complexes.
GO:0033558 protein lysine deacetylase activity	IEA GO_REF:0000120	ACCEPT	Summary: HDAC6 is a protein lysine deacetylase that removes acetyl groups from lysine residues of non-histone substrates. Reason: Core molecular function. This is the most accurate term for HDAC6's primary enzymatic activity.
GO:0042903 tubulin deacetylase activity	IEA GO_REF:0000107	ACCEPT	Summary: HDAC6 deacetylates alpha-tubulin at K40. Reason: Core molecular function [PMID:12024216]. Supporting Evidence: PMID:12024216 HDAC6, functions as a tubulin deacetylase
GO:0043005 neuron projection	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 localizes to neuron projections (axons, dendrites). Reason: Specialized neuronal localization.
GO:0043130 ubiquitin binding	IEA GO_REF:0000107	ACCEPT	Summary: HDAC6 binds ubiquitin via its C-terminal ZnF-UBP domain. Reason: Core molecular function. The ZnF-UBP domain binds polyubiquitinated proteins and is essential for HDAC6's role in aggresome formation [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors
GO:0044297 cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 localizes to the cell body. Reason: Very general localization term.
GO:0048156 tau protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 interacts with tau protein. Tau can inhibit HDAC6 deacetylase activity [PMID:19457097]. Reason: Tau is a regulatory interactor of HDAC6 rather than a core functional binding partner. Supporting Evidence: PMID:19457097 tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity with a consequent increase in tubulin acetylation
GO:0048487 beta-tubulin binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 binds tubulin including beta-tubulin as part of microtubule binding. Reason: The primary substrate is alpha-tubulin K40. Beta-tubulin binding is likely incidental to microtubule association.
GO:0051646 mitochondrion localization	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: HDAC6 can affect mitochondrial localization/transport through its effects on microtubule dynamics and axonal transport. Reason: Downstream effect of HDAC6's role in microtubule regulation rather than direct mitochondrial localization function.
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 has E3 ubiquitin ligase activity mediated by its histone deacetylase domain 1. Reason: While HDAC6 does have ubiquitin ligase activity (for MSH2), this is a secondary function. The deacetylase activity is the primary enzymatic function.
GO:1905091 positive regulation of type 2 mitophagy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: HDAC6 participates in parkin-mediated mitophagy through its ubiquitin-binding function. Reason: Specialized autophagy function related to HDAC6's broader role in aggrephagy/autophagy.
GO:0005813 centrosome	IDA GO_REF:0000052	ACCEPT	Summary: HDAC6 localizes to the centrosome based on immunofluorescence data. Reason: Core localization for cilium-related function [PMID:26246421].
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: HDAC6 localizes to cytosol based on immunofluorescence data. Reason: Core localization.
GO:0036064 ciliary basal body	IDA GO_REF:0000052	ACCEPT	Summary: HDAC6 localizes to the ciliary basal body based on immunofluorescence data. Reason: Core localization for cilium disassembly function [PMID:17604723, PMID:26246421].
GO:0034605 cellular response to heat	TAS Reactome:R-HSA-3371511	KEEP AS NON CORE	Summary: HDAC6 participates in heat shock response through HSF1 activation pathway. Reason: HDAC6's role in heat shock response is related to its HSP90 deacetylation function. The heat shock response is a downstream process.
GO:0060271 cilium assembly	TAS Reactome:R-HSA-5620920	MODIFY	Summary: HDAC6 affects cilium assembly through its role in cilium disassembly via tubulin deacetylation. Reason: HDAC6 promotes cilium DISassembly rather than assembly. The term should be cilium disassembly. Proposed replacements: cilium disassembly
GO:0042903 tubulin deacetylase activity	IMP PMID:19457097 Tau--an inhibitor of deacetylase HDAC6 function.	ACCEPT	Summary: Study showing tau inhibits HDAC6 tubulin deacetylase activity. Reason: Core molecular function. Supports HDAC6's role as a tubulin deacetylase. Supporting Evidence: PMID:19457097 tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity
GO:0060632 regulation of microtubule-based movement	IDA PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	ACCEPT	Summary: HDAC6 regulates microtubule-based movement through tubulin deacetylation. Reason: Core function directly related to tubulin deacetylation. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0007173 epidermal growth factor receptor signaling pathway	IMP PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	KEEP AS NON CORE	Summary: HDAC6 participates in EGFR signaling. Reason: Downstream signaling effect, not a core function of HDAC6. Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0010727 negative regulation of hydrogen peroxide metabolic process	IMP PMID:18606987 HDAC6 is a specific deacetylase of peroxiredoxins and is inv...	KEEP AS NON CORE	Summary: HDAC6 deacetylates peroxiredoxins, affecting their H2O2 reducing activity. Reason: Downstream effect of peroxiredoxin deacetylation rather than core function. Supporting Evidence: PMID:18606987 HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation
GO:0019899 enzyme binding	IPI PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	KEEP AS NON CORE	Summary: HDAC6 binds enzymes including farnesyltransferase. Reason: Generic binding term, context-specific regulatory interaction. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0033148 positive regulation of intracellular estrogen receptor signaling pathway	IMP PMID:18316616 Selective inhibition of histone deacetylase 2 silences proge...	KEEP AS NON CORE	Summary: HDAC6 affects estrogen receptor signaling. Reason: Downstream signaling effect through HSP90 deacetylation or other mechanisms. Supporting Evidence: PMID:18316616 Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling.
GO:0033558 protein lysine deacetylase activity	IMP PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	ACCEPT	Summary: Experimental evidence for protein lysine deacetylase activity. Reason: Core molecular function. Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0033558 protein lysine deacetylase activity	TAS PMID:28386764 Roles of tau protein in health and disease.	ACCEPT	Summary: Review article supporting protein lysine deacetylase activity. Reason: Core molecular function. Supporting Evidence: PMID:28386764 Epub 2017 Apr 6. Roles of tau protein in health and disease.
GO:0036479 peroxidase inhibitor activity	IMP PMID:18606987 HDAC6 is a specific deacetylase of peroxiredoxins and is inv...	KEEP AS NON CORE	Summary: HDAC6 deacetylates peroxiredoxins, decreasing their peroxidase activity. Reason: Downstream effect of peroxiredoxin deacetylation. HDAC6 is not itself an inhibitor but deacetylates peroxiredoxins which modulates their activity. Supporting Evidence: PMID:18606987 Acetylation of Prx increases its reducing activity... Thus, HDAC6 and Prx are targets for modulating intracellular redox status
GO:0042030 ATPase inhibitor activity	IMP PMID:15916966 HDAC6 regulates Hsp90 acetylation and chaperone-dependent ac...	KEEP AS NON CORE	Summary: HDAC6 deacetylates HSP90, affecting its ATPase-dependent chaperone activity. Reason: Indirect effect through HSP90 deacetylation. HDAC6 modulates HSP90 function but is not itself an ATPase inhibitor. Supporting Evidence: PMID:15916966 HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity
GO:0032461 positive regulation of protein oligomerization	IMP PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determin...	KEEP AS NON CORE	Summary: HDAC6 affects tau aggregation/oligomerization through deacetylation of KXGS motifs. Reason: Context-specific effect on tau aggregation in neurodegeneration. Supporting Evidence: PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.
GO:0033558 protein lysine deacetylase activity	IMP PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determin...	ACCEPT	Summary: HDAC6 deacetylates tau protein at KXGS motifs. Reason: Core molecular function. Supporting Evidence: PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.
GO:0033558 protein lysine deacetylase activity	IDA PMID:31857589 Requirement for p62 acetylation in the aggregation of ubiqui...	ACCEPT	Summary: HDAC6 deacetylates p62/SQSTM1. Reason: Core molecular function. Demonstrates HDAC6 deacetylates p62 which regulates autophagy. Supporting Evidence: PMID:31857589 Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress.
GO:1905336 negative regulation of aggrephagy	IDA PMID:31857589 Requirement for p62 acetylation in the aggregation of ubiqui...	MODIFY	Summary: HDAC6 deacetylation of p62 regulates aggrephagy. Reason: HDAC6 actually promotes aggrephagy through aggresome formation. The p62 deacetylation may have complex regulatory effects but HDAC6's overall role is to promote aggrephagy. Proposed replacements: positive regulation of aggrephagy Supporting Evidence: PMID:31857589 Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress.
GO:0005737 cytoplasm	IDA PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDA...	ACCEPT	Summary: Direct experimental evidence for cytoplasmic localization. Reason: Core localization. Supporting Evidence: PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.
GO:0005813 centrosome	IDA PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDA...	ACCEPT	Summary: Direct experimental evidence for centrosome localization. Reason: Core localization for cilium function. Supporting Evidence: PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.
GO:0036064 ciliary basal body	IDA PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDA...	ACCEPT	Summary: Direct experimental evidence for ciliary basal body localization. Reason: Core localization for cilium disassembly function. Supporting Evidence: PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.
GO:0061523 cilium disassembly	IDA PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDA...	ACCEPT	Summary: HDAC6 promotes cilium disassembly via deacetylation of alpha-tubulin and cortactin. Reason: Core biological process. HDAC6-mediated tubulin deacetylation is required for cilium disassembly [PMID:17604723, PMID:26246421]. Supporting Evidence: PMID:17604723 phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly PMID:26246421 Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.
GO:0045814 negative regulation of gene expression, epigenetic	IMP PMID:24413532 Differential regulation of estrogen receptor α expression in...	KEEP AS NON CORE	Summary: HDAC6 involved in MTA1-mediated epigenetic regulation of ESR1. Reason: Context-specific effect in breast cancer, not a core function. Supporting Evidence: PMID:24413532 2014 Jan 10. Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
GO:0005515 protein binding	IPI PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of th...	MODIFY	Summary: HDAC6 interacts with Aurora A and HEF1 at the ciliary basal body. Reason: 'Protein binding' is uninformative. The specific interaction with Aurora A kinase is more informative. Proposed replacements: phosphoprotein binding Supporting Evidence: PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of the primary cilium.
GO:0036064 ciliary basal body	IDA PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of th...	ACCEPT	Summary: HDAC6 localizes to ciliary basal body. Reason: Core localization for cilium function [PMID:17604723]. Supporting Evidence: PMID:17604723 Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6
GO:0061523 cilium disassembly	IMP PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of th...	ACCEPT	Summary: HDAC6 is required for cilium disassembly. Reason: Core biological process [PMID:17604723]. Supporting Evidence: PMID:17604723 this pathway is both necessary and sufficient for ciliary resorption
GO:0051787 misfolded protein binding	EXP PMID:17785525 HDAC6 controls major cell response pathways to cytotoxic acc...	ACCEPT	Summary: HDAC6 binds misfolded proteins through its ZnF-UBP domain recognizing polyubiquitin chains. Reason: Core molecular function. Essential for HDAC6's role in aggresome formation [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors PMID:17785525 HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.
GO:0019896 axonal transport of mitochondrion	IGI PMID:28105056 HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial ...	KEEP AS NON CORE	Summary: HDAC6 affects axonal mitochondrial transport through effects on microtubule acetylation. Reason: Specialized neuronal function related to microtubule regulation. Supporting Evidence: PMID:28105056 HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation.
GO:0001222 transcription corepressor binding	IPI PMID:12535528 Ligand-dependent nuclear receptor corepressor LCoR functions...	KEEP AS NON CORE	Summary: HDAC6 interacts with LCoR transcription corepressor. Reason: Context-specific interaction in transcriptional regulation, not a core function. Supporting Evidence: PMID:12535528 Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms.
GO:0042903 tubulin deacetylase activity	EXP PMID:12024216 HDAC6 is a microtubule-associated deacetylase.	ACCEPT	Summary: Original discovery of HDAC6 as a tubulin deacetylase. Reason: Core molecular function. This is the seminal paper establishing HDAC6 as the tubulin deacetylase. Supporting Evidence: PMID:12024216 HDAC6, functions as a tubulin deacetylase... In vitro, purified HDAC6 potently deacetylates alpha-tubulin in assembled microtubules
GO:0005515 protein binding	IPI PMID:20308065 TPPP/p25 promotes tubulin acetylation by inhibiting histone ...	KEEP AS NON CORE	Summary: HDAC6 interacts with TPPP/p25 which inhibits its tubulin deacetylase activity. Reason: 'Protein binding' is uninformative. TPPP is a regulatory interactor. Supporting Evidence: PMID:20308065 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6.
GO:0042903 tubulin deacetylase activity	IDA PMID:20308065 TPPP/p25 promotes tubulin acetylation by inhibiting histone ...	ACCEPT	Summary: Direct demonstration of HDAC6 tubulin deacetylase activity. Reason: Core molecular function. Supporting Evidence: PMID:20308065 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6.
GO:0090042 tubulin deacetylation	IDA PMID:20308065 TPPP/p25 promotes tubulin acetylation by inhibiting histone ...	ACCEPT	Summary: Direct demonstration of HDAC6-mediated tubulin deacetylation. Reason: Core biological process. Supporting Evidence: PMID:20308065 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6.
GO:0090042 tubulin deacetylation	IDA PMID:23093407 Rho-associated coiled-coil kinase (ROCK) protein controls mi...	ACCEPT	Summary: ROCK signaling pathway regulates HDAC6-mediated tubulin deacetylation. Reason: Core biological process. Supporting Evidence: PMID:23093407 2012 Oct 23. Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration.
GO:0031333 negative regulation of protein-containing complex assembly	IMP PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determin...	KEEP AS NON CORE	Summary: HDAC6 affects protein complex assembly through deacetylation. Reason: Context-specific effect, likely related to tau aggregation studies. Supporting Evidence: PMID:23962722 Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.
GO:0006476 protein deacetylation	IDA PMID:28516954 Histone deacetylase 10 structure and molecular function as a...	UNDECIDED	Summary: Note: PMID:28516954 is about HDAC10, not HDAC6. This may be an error. Reason: Need to verify this annotation - the PMID is about HDAC10 structure and polyamine deacetylation, which may have been mis-annotated to HDAC6. Supporting Evidence: PMID:28516954 Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.
GO:0033558 protein lysine deacetylase activity	IDA PMID:28516954 Histone deacetylase 10 structure and molecular function as a...	UNDECIDED	Summary: Note: PMID:28516954 is about HDAC10, not HDAC6. Reason: Need to verify - may be annotation error as this paper is about HDAC10. Supporting Evidence: PMID:28516954 Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.
GO:0047611 acetylspermidine deacetylase activity	IDA NOT PMID:28516954 Histone deacetylase 10 structure and molecular function as a...	ACCEPT	Summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 does NOT have acetylspermidine deacetylase activity - this activity is specific to HDAC10. Reason: This is correctly a NOT annotation. The paper PMID:28516954 established that polyamine deacetylation is a function of HDAC10, not HDAC6. The negative annotation correctly reflects that HDAC6 lacks this activity. Supporting Evidence: PMID:28516954 Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.
GO:0106047 polyamine deacetylation	IDA NOT PMID:28516954 Histone deacetylase 10 structure and molecular function as a...	ACCEPT	Summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 is NOT involved in polyamine deacetylation - this activity is specific to HDAC10. Reason: This is correctly a NOT annotation. The paper PMID:28516954 established that polyamine deacetylation is a function of HDAC10, not HDAC6. Supporting Evidence: PMID:28516954 Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.
GO:0106048 spermidine deacetylation	IDA NOT PMID:28516954 Histone deacetylase 10 structure and molecular function as a...	ACCEPT	Summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 is NOT involved in spermidine deacetylation - this activity is specific to HDAC10. Reason: This is correctly a NOT annotation. The paper PMID:28516954 established that spermidine deacetylation is a function of HDAC10, not HDAC6. Supporting Evidence: PMID:28516954 Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.
GO:0048156 tau protein binding	NAS PMID:28386764 Roles of tau protein in health and disease.	KEEP AS NON CORE	Summary: Review article discussing tau-HDAC6 interaction. Reason: Tau is a regulatory interactor rather than core functional partner. Supporting Evidence: PMID:28386764 Epub 2017 Apr 6. Roles of tau protein in health and disease.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:24413532 Differential regulation of estrogen receptor α expression in...	MARK AS OVER ANNOTATED	Summary: HDAC6 involvement in transcriptional regulation of ESR1. Reason: HDAC6 is primarily a cytoplasmic deacetylase. Direct DNA binding is not a core function. This may reflect an indirect effect or context-specific nuclear function. Supporting Evidence: PMID:24413532 2014 Jan 10. Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
GO:0005737 cytoplasm	TAS PMID:19457097 Tau--an inhibitor of deacetylase HDAC6 function.	ACCEPT	Summary: Cytoplasmic localization noted in tau-HDAC6 interaction study. Reason: Core localization. HDAC6 is well-established as a cytoplasmic protein. Supporting Evidence: PMID:19457097 Epub 2009 May 7. Tau--an inhibitor of deacetylase HDAC6 function.
GO:0016235 aggresome	TAS PMID:19457097 Tau--an inhibitor of deacetylase HDAC6 function.	ACCEPT	Summary: HDAC6 localizes to aggresomes. Reason: Core localization. HDAC6 is a component of the aggresome [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6, a microtubule-associated deacetylase, is a component of the aggresome PMID:19457097 Epub 2009 May 7. Tau--an inhibitor of deacetylase HDAC6 function.
GO:0048156 tau protein binding	ISS PMID:19457097 Tau--an inhibitor of deacetylase HDAC6 function.	KEEP AS NON CORE	Summary: Tau binds and inhibits HDAC6. Reason: Tau is a regulatory interactor. Supporting Evidence: PMID:19457097 tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity
GO:0048156 tau protein binding	TAS PMID:19457097 Tau--an inhibitor of deacetylase HDAC6 function.	KEEP AS NON CORE	Summary: Tau binds HDAC6. Reason: Duplicate - tau is a regulatory interactor. Supporting Evidence: PMID:19457097 Epub 2009 May 7. Tau--an inhibitor of deacetylase HDAC6 function.
GO:0005515 protein binding	IPI PMID:25422469 Disruption of FAT10-MAD2 binding inhibits tumor progression.	KEEP AS NON CORE	Summary: HDAC6 interacts with UBD/FAT10. Reason: UBD is a ubiquitin-like modifier; interaction related to ubiquitin binding function. Supporting Evidence: PMID:25422469 Disruption of FAT10-MAD2 binding inhibits tumor progression.
GO:0005515 protein binding	IPI PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin pro...	KEEP AS NON CORE	Summary: HDAC6 interacts with FAM65B and dysferlin during myogenesis. Reason: Context-specific interaction during myogenic differentiation. Supporting Evidence: PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin protein complex during myogenic cell differentiation.
GO:0005515 protein binding	IPI PMID:27556504 FAM65B controls the proliferation of transformed and primary...	KEEP AS NON CORE	Summary: FAM65B interaction with HDAC6 in T cell proliferation. Reason: Context-specific interaction in immune cells. Supporting Evidence: PMID:27556504 FAM65B controls the proliferation of transformed and primary T cells.
GO:0005737 cytoplasm	IDA PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin pro...	ACCEPT	Summary: Cytoplasmic localization during myogenic differentiation. Reason: Core localization. Supporting Evidence: PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin protein complex during myogenic cell differentiation.
GO:0016241 regulation of macroautophagy	IMP PMID:16192271 HDAC6 and microtubules are required for autophagic degradati...	ACCEPT	Summary: HDAC6 regulates macroautophagy of aggregated proteins. Reason: Core function. HDAC6 is required for autophagic degradation of aggregated proteins [PMID:16192271]. Supporting Evidence: PMID:16192271 HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation
GO:0061734 type 2 mitophagy	IGI PMID:20457763 Disease-causing mutations in parkin impair mitochondrial ubi...	KEEP AS NON CORE	Summary: HDAC6 participates in parkin-mediated mitophagy. Reason: Specialized autophagy function related to parkin pathway. Supporting Evidence: PMID:20457763 May 10. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.
GO:0005771 multivesicular body	TAS PMID:25548531 ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.	KEEP AS NON CORE	Summary: HDAC6 involved in autophagy-related membrane trafficking. Reason: Related to autophagy function but not core localization. Supporting Evidence: PMID:25548531 Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.
GO:0010506 regulation of autophagy	TAS PMID:25548531 ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.	ACCEPT	Summary: HDAC6 regulates autophagy. Reason: Core function - autophagy regulation is a key HDAC6 function. Supporting Evidence: PMID:25548531 Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.
GO:1903146 regulation of autophagy of mitochondrion	TAS PMID:25548531 ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.	KEEP AS NON CORE	Summary: HDAC6 involved in mitophagy regulation. Reason: Specialized autophagy function. Supporting Evidence: PMID:25548531 Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.
GO:0031647 regulation of protein stability	IMP PMID:23580651 HDAC6 regulates mutant SOD1 aggregation through two SMIR mot...	KEEP AS NON CORE	Summary: HDAC6 regulates mutant SOD1 aggregation through tubulin acetylation. Reason: Context-specific effect in neurodegeneration models. Supporting Evidence: PMID:23580651 2013 Apr 11. HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation.
GO:0031625 ubiquitin protein ligase binding	IPI PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy.	KEEP AS NON CORE	Summary: HDAC6 interacts with Ambra1 and ubiquitin ligases in mitophagy. Reason: Interaction related to autophagy pathway. Supporting Evidence: PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy.
GO:0030424 axon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: HDAC6 localizes to axons based on sequence similarity. Reason: Specialized neuronal localization.
GO:0030425 dendrite	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: HDAC6 localizes to dendrites based on sequence similarity. Reason: Specialized neuronal localization.
GO:0043204 perikaryon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: HDAC6 localizes to perikaryon based on sequence similarity. Reason: Specialized neuronal localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-5324632	ACCEPT	Summary: Cytosol localization in HSF1 activation pathway. Reason: Core localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-5618331	ACCEPT	Summary: Cytosol localization in microtubule deacetylation pathway. Reason: Core localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646348	ACCEPT	Summary: Cytosol localization in aggrephagy pathway. Reason: Core localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646679	ACCEPT	Summary: Cytosol localization in aggresome formation pathway. Reason: Core localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646685	ACCEPT	Summary: Cytosol localization in aggresome pathway. Reason: Core localization.
GO:0004407 histone deacetylase activity	IMP PMID:23322205 A novel small molecule hydroxamate preferentially inhibits H...	MODIFY	Summary: Study testing HDAC6 inhibitors. Reason: HDAC6 is more accurately described as a protein lysine deacetylase. It primarily deacetylates non-histone substrates. Proposed replacements: protein lysine deacetylase activity Supporting Evidence: PMID:23322205 Jan 15. A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.
GO:0005515 protein binding	IPI PMID:17872950 Critical and functional regulation of CHOP (C/EBP homologous...	KEEP AS NON CORE	Summary: HDAC6 interacts with CHOP/DDIT3. Reason: Context-specific interaction in ER stress response. Supporting Evidence: PMID:17872950 2007 Sep 14. Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion.
GO:0035967 cellular response to topologically incorrect protein	IMP PMID:16192271 HDAC6 and microtubules are required for autophagic degradati...	ACCEPT	Summary: HDAC6 mediates response to misfolded proteins by facilitating aggresome formation. Reason: Core function. HDAC6 is essential for cellular response to misfolded protein accumulation [PMID:14675537, PMID:16192271]. Supporting Evidence: PMID:14675537 cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins PMID:16192271 2005 Sep 28. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.
GO:0005515 protein binding	IPI PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ...	KEEP AS NON CORE	Summary: HDAC6 interacts with BBIP1, a BBSome subunit, affecting ciliogenesis. Reason: Interaction related to cilium function. Supporting Evidence: PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, and acetylation.
GO:0005634 nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Nuclear localization based on sequence similarity. Reason: HDAC6 is predominantly cytoplasmic but can shuttle to nucleus under specific conditions.
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: Cytosol localization based on sequence similarity. Reason: Core localization.
GO:0008017 microtubule binding	ISS GO_REF:0000024	ACCEPT	Summary: Microtubule binding based on sequence similarity. Reason: Core molecular function.
GO:0042903 tubulin deacetylase activity	ISS GO_REF:0000024	ACCEPT	Summary: Tubulin deacetylase activity based on sequence similarity. Reason: Core molecular function.
GO:0090042 tubulin deacetylation	ISS GO_REF:0000024	ACCEPT	Summary: Tubulin deacetylation based on sequence similarity. Reason: Core biological process.
GO:0005515 protein binding	IPI PMID:19033385 FAT10 interacts with HDAC6 and localizes to aggresomes	KEEP AS NON CORE	Summary: HDAC6 interacts with FAT10/UBD under proteasome inhibition. Reason: Interaction related to ubiquitin-like modifier system. Supporting Evidence: PMID:19033385 Nov 25. The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition.
GO:0004407 histone deacetylase activity	IDA PMID:10220385 Three proteins define a class of human histone deacetylases ...	MODIFY	Summary: Original identification of HDAC6 as a histone deacetylase family member. Reason: While HDAC6 was originally identified as an HDAC, subsequent work has shown it primarily deacetylates non-histone substrates. Should be protein lysine deacetylase activity. Proposed replacements: protein lysine deacetylase activity Supporting Evidence: PMID:10220385 Three proteins define a class of human histone deacetylases related to yeast Hda1p.
GO:0070840 dynein complex binding	IDA PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 binds dynein motors to transport misfolded proteins to aggresomes. Reason: Core molecular function. Dynein binding is essential for HDAC6's role in aggresome formation [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes
GO:0070842 aggresome assembly	IMP PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 is required for aggresome assembly. Reason: Core biological process [PMID:14675537]. Supporting Evidence: PMID:14675537 cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly
GO:0070845 polyubiquitinated misfolded protein transport	IMP PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 mediates transport of polyubiquitinated misfolded proteins to aggresomes. Reason: Core biological process [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes
GO:0006515 protein quality control for misfolded or incompletely synthesized proteins	IMP PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 is essential for cellular protein quality control by facilitating aggresome formation and autophagic clearance of misfolded proteins. Reason: Core biological process [PMID:14675537]. Supporting Evidence: PMID:14675537 These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress
GO:0016235 aggresome	IDA PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 localizes to aggresomes. Reason: Core localization [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6, a microtubule-associated deacetylase, is a component of the aggresome
GO:0031593 polyubiquitin modification-dependent protein binding	IDA PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 binds polyubiquitinated proteins via its ZnF-UBP domain. Reason: Core molecular function [PMID:14675537]. Supporting Evidence: PMID:14675537 HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors
GO:0048156 tau protein binding	IDA PMID:18636984 Histone deacetylase 6 interacts with the microtubule-associa...	KEEP AS NON CORE	Summary: HDAC6 binds tau protein. Reason: Tau is a regulatory interactor. Supporting Evidence: PMID:18636984 Epub 2008 Jul 12. Histone deacetylase 6 interacts with the microtubule-associated protein tau.
GO:0051788 response to misfolded protein	IMP PMID:14675537 The deacetylase HDAC6 regulates aggresome formation and cell...	ACCEPT	Summary: HDAC6 mediates cellular response to misfolded proteins. Reason: Core biological process [PMID:14675537]. Supporting Evidence: PMID:14675537 These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress
GO:0060765 regulation of androgen receptor signaling pathway	TAS PMID:18852123 Genistein down-regulates androgen receptor by modulating HDA...	KEEP AS NON CORE	Summary: HDAC6 affects androgen receptor signaling through HSP90. Reason: Downstream effect of HSP90 deacetylation. Supporting Evidence: PMID:18852123 Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function.
GO:0006886 intracellular protein transport	IMP PMID:16192271 HDAC6 and microtubules are required for autophagic degradati...	ACCEPT	Summary: HDAC6 involved in transport of aggregated proteins via microtubules. Reason: Core function - HDAC6 mediates retrograde transport of misfolded proteins to aggresomes [PMID:14675537, PMID:16192271]. Supporting Evidence: PMID:16192271 HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation
GO:0016234 inclusion body	IDA PMID:16192271 HDAC6 and microtubules are required for autophagic degradati...	ACCEPT	Summary: HDAC6 localizes to inclusion bodies/aggresomes. Reason: Core localization related to aggresome function. Supporting Evidence: PMID:16192271 2005 Sep 28. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.
GO:0032418 lysosome localization	IMP PMID:16192271 HDAC6 and microtubules are required for autophagic degradati...	KEEP AS NON CORE	Summary: HDAC6 affects lysosome localization during autophagy. Reason: Downstream effect of autophagy regulation. Supporting Evidence: PMID:16192271 2005 Sep 28. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.
GO:0070301 cellular response to hydrogen peroxide	IMP PMID:18606987 HDAC6 is a specific deacetylase of peroxiredoxins and is inv...	KEEP AS NON CORE	Summary: HDAC6 affects cellular response to H2O2 through peroxiredoxin deacetylation. Reason: Downstream effect of peroxiredoxin deacetylation. Supporting Evidence: PMID:18606987 HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation.
GO:0005875 microtubule associated complex	IDA PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	ACCEPT	Summary: HDAC6 associates with microtubule complexes. Reason: Core localization. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0005901 caveola	IDA PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	KEEP AS NON CORE	Summary: HDAC6 localizes to caveolae in EGFR signaling context. Reason: Context-specific localization in EGFR signaling. Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0008013 beta-catenin binding	IPI PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	KEEP AS NON CORE	Summary: HDAC6 binds beta-catenin. Reason: Signaling pathway interaction. Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0008017 microtubule binding	IDA PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	ACCEPT	Summary: Direct demonstration of HDAC6 microtubule binding. Reason: Core molecular function. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0010634 positive regulation of epithelial cell migration	IMP PMID:12024216 HDAC6 is a microtubule-associated deacetylase.	ACCEPT	Summary: HDAC6 promotes cell motility through tubulin deacetylation. Reason: Core function - HDAC6 regulates cell motility through effects on microtubule dynamics [PMID:12024216]. Supporting Evidence: PMID:12024216 overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility
GO:0031252 cell leading edge	IDA PMID:12024216 HDAC6 is a microtubule-associated deacetylase.	ACCEPT	Summary: HDAC6 localizes to cell leading edge. Reason: Relevant to cell motility function [PMID:12024216]. Supporting Evidence: PMID:12024216 Acetylated alpha-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts
GO:0042903 tubulin deacetylase activity	IDA PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	ACCEPT	Summary: Direct demonstration of tubulin deacetylase activity. Reason: Core molecular function. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0043014 alpha-tubulin binding	IDA PMID:19228685 The protein farnesyltransferase regulates HDAC6 activity in ...	ACCEPT	Summary: HDAC6 binds alpha-tubulin, its primary substrate. Reason: Core molecular function - alpha-tubulin is the primary substrate. Supporting Evidence: PMID:19228685 2009 Feb 18. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
GO:0043242 negative regulation of protein-containing complex disassembly	IMP PMID:15916966 HDAC6 regulates Hsp90 acetylation and chaperone-dependent ac...	KEEP AS NON CORE	Summary: HDAC6 affects HSP90 complex stability through deacetylation. Reason: Downstream effect of HSP90 deacetylation. Supporting Evidence: PMID:15916966 HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.
GO:0045861 negative regulation of proteolysis	IMP PMID:18356165 HDAC6 is required for epidermal growth factor-induced beta-c...	KEEP AS NON CORE	Summary: HDAC6 affects proteolysis in EGFR signaling context. Reason: Context-specific effect. Supporting Evidence: PMID:18356165 2008 Mar 20. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:12024216 HDAC6 is a microtubule-associated deacetylase.	ACCEPT	Summary: HDAC6 localizes to perinuclear region (MTOC/aggresome region). Reason: Relevant to aggresome function - aggresomes form at the MTOC in the perinuclear region. Supporting Evidence: PMID:12024216 HDAC6 is a microtubule-associated deacetylase.
GO:0051879 Hsp90 protein binding	IDA PMID:15916966 HDAC6 regulates Hsp90 acetylation and chaperone-dependent ac...	ACCEPT	Summary: HDAC6 binds and deacetylates HSP90. Reason: Core molecular function - HSP90 is a major HDAC6 substrate [PMID:15916966]. Supporting Evidence: PMID:15916966 HDAC6 functions as an Hsp90 deacetylase
GO:0005874 microtubule	IDA PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	ACCEPT	Summary: HDAC6 associates with microtubules (study on SIRT2-HDAC6 interaction). Reason: Core localization. Supporting Evidence: PMID:12620231 SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase
GO:0042903 tubulin deacetylase activity	IDA PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	ACCEPT	Summary: HDAC6 tubulin deacetylase activity (study on SIRT2-HDAC6 interaction). Reason: Core molecular function. Supporting Evidence: PMID:12620231 HDAC6, another tubulin deacetylase
GO:0042826 histone deacetylase binding	IPI PMID:12620231 The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin...	KEEP AS NON CORE	Summary: HDAC6 interacts with SIRT2. Reason: Interaction with another tubulin deacetylase (SIRT2) - regulatory relationship. Supporting Evidence: PMID:12620231 SIRT2 colocalizes and interacts in vivo with HDAC6
GO:0005737 cytoplasm	ISS PMID:11861901 Identification of HDAC10, a novel class II human histone dea...	ACCEPT	Summary: Cytoplasmic localization by sequence similarity. Reason: Core localization. Supporting Evidence: PMID:11861901 Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain.
GO:0019899 enzyme binding	ISS PMID:11861901 Identification of HDAC10, a novel class II human histone dea...	KEEP AS NON CORE	Summary: HDAC6 binds other enzymes. Reason: Generic binding term. Supporting Evidence: PMID:11861901 Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain.
GO:0045892 negative regulation of DNA-templated transcription	ISS PMID:11861901 Identification of HDAC10, a novel class II human histone dea...	MARK AS OVER ANNOTATED	Summary: HDAC6 may affect transcription through deacetylase activity. Reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone substrates. Its role in transcriptional regulation is indirect and not a core function. Supporting Evidence: PMID:11861901 Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain.
GO:0000118 histone deacetylase complex	IDA PMID:11948178 Cloning and functional characterization of HDAC11, a novel m...	KEEP AS NON CORE	Summary: HDAC6 interacts with HDAC11. Reason: While HDAC6 can interact with other HDACs, it does not primarily function as part of nuclear HDAC complexes. Supporting Evidence: PMID:11948178 2002 Apr 10. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family.

Core Functions

HDAC6 deacetylates alpha-tubulin at K40, regulating microtubule stability and dynamics. This is one of the best-characterized functions of HDAC6.

Molecular Function:

tubulin deacetylase activity

HDAC6 is a Zn2+-dependent deacetylase that removes acetyl groups from lysine residues of various non-histone substrates including tubulin, HSP90, cortactin, peroxiredoxins, and other cytoplasmic proteins.

Molecular Function:

protein lysine deacetylase activity

HDAC6 binds and deacetylates HSP90, regulating its chaperone activity. This affects client protein maturation including steroid hormone receptors.

Molecular Function:

Hsp90 protein binding

HDAC6 binds ubiquitin via its C-terminal ZnF-UBP domain. This is essential for recognizing polyubiquitinated misfolded proteins and transporting them to aggresomes.

Molecular Function:

ubiquitin binding

HDAC6 is essential for aggresome formation. It binds polyubiquitinated misfolded proteins via its ZnF-UBP domain and recruits dynein motors for retrograde transport to the MTOC.

Molecular Function:

dynein complex binding

Directly Involved In:

aggresome assembly

HDAC6 promotes cilium disassembly through deacetylation of alpha-tubulin and cortactin at the ciliary basal body. This is regulated by Aurora A phosphorylation.

Molecular Function:

tubulin deacetylase activity

Directly Involved In:

cilium disassembly

References

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, accompanied by conservative changes to GO terms applied by UniProt

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, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10220385

Three proteins define a class of human histone deacetylases related to yeast Hda1p.

Original identification of HDAC6 as a histone deacetylase family member

PMID:11861901

Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain.

PMID:11948178

Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family.

HDAC6 interacts with HDAC11

PMID:12024216

HDAC6 is a microtubule-associated deacetylase.

HDAC6 is the tubulin deacetylase
HDAC6 is cytoplasmic and associates with microtubules
HDAC6 promotes cell motility through tubulin deacetylation

PMID:12354939

Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes.

HDAC6 ZnF-UBP domain binds polyubiquitin

PMID:12535528

Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms.

PMID:12620231

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

HDAC6 interacts with SIRT2, another tubulin deacetylase

PMID:14675537

The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.

HDAC6 binds polyubiquitinated misfolded proteins and dynein motors
HDAC6 is essential for aggresome formation
HDAC6 is crucial for managing misfolded protein stress

PMID:15916966

HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.

HDAC6 deacetylates HSP90 to regulate its chaperone activity

PMID:16192271

HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.

HDAC6-dependent retrograde transport required for autophagy

PMID:16919237

Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone.

PMID:17604723

HEF1-dependent Aurora A activation induces disassembly of the primary cilium.

HDAC6 phosphorylation by Aurora A promotes cilium disassembly
HDAC6 localizes to ciliary basal body

PMID:17785525

HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.

PMID:17872950

Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion.

PMID:18316616

Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling.

PMID:18356165

HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.

PMID:18606987

HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation.

HDAC6 deacetylates peroxiredoxins, affecting their H2O2 reducing activity

PMID:18636984

Histone deacetylase 6 interacts with the microtubule-associated protein tau.

PMID:18852123

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function.

PMID:19033385

FAT10 interacts with HDAC6 and localizes to aggresomes

PMID:19036992

Direct binding with histone deacetylase 6 mediates the reversible recruitment of parkin to the centrosome.

PMID:19081074

A BBSome subunit links ciliogenesis, microtubule stability, and acetylation.

PMID:19167333

A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons.

PMID:19228685

The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.

PMID:19457097

Tau--an inhibitor of deacetylase HDAC6 function.

Tau binds HDAC6 and inhibits its tubulin deacetylase activity

PMID:19893491

CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.

PMID:20029029

Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.

PMID:20308065

TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6.

PMID:20457763

Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.

PMID:21220424

Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6.

PMID:21532619

The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6.

PMID:21753002

Parkin interacts with Ambra1 to induce mitophagy.

PMID:21847094

Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.

PMID:21952047

PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin.

PMID:22193721

A novel GRK2/HDAC6 interaction modulates cell spreading and motility.

PMID:22645275

Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity.

PMID:23084749

Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation.

PMID:23093407

Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration.

PMID:23322205

A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.

PMID:23580651

HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation.

PMID:23962722

Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.

PMID:24413532

Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.

PMID:24658140

The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells.

PMID:24687993

Fam65b is important for formation of the HDAC6-dysferlin protein complex during myogenic cell differentiation.

PMID:25422469

Disruption of FAT10-MAD2 binding inhibits tumor progression.

PMID:25548531

ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.

PMID:26246421

Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.

HDAC6 deacetylates both alpha-tubulin and cortactin for cilium disassembly

PMID:27556504

FAM65B controls the proliferation of transformed and primary T cells.

PMID:28105056

HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation.

PMID:28386764

Roles of tau protein in health and disease.

PMID:28516954

Histone deacetylase 10 structure and molecular function as a polyamine deacetylase.

Note - this paper is about HDAC10, not HDAC6

PMID:29281743

HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes.

PMID:31857589

Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress.

HDAC6 deacetylates p62/SQSTM1

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

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

Reactome:R-HSA-3371511

HSF1 activation

Reactome:R-HSA-5324632

Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates

Reactome:R-HSA-5618331

HDAC6 deacetylates microtubules

Reactome:R-HSA-5620920

Cargo trafficking to the periciliary membrane

Reactome:R-HSA-9646348

PolyUb-Misfolded Proteins:HDAC6 bind dynein motor

Reactome:R-HSA-9646679

PolyUb-Misfolded proteins bind vimentin to form aggresome

Reactome:R-HSA-9646685

Aggresome dissociates from dynein and microtubule

file:human/HDAC6/HDAC6-deep-research-falcon.md

Deep research report on HDAC6

📚 Additional Documentation

Deep Research Falcon

(HDAC6-deep-research-falcon.md)

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gene_id: HDAC6
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uniprot_accession: Q9UBN7
protein_description: 'RecName: Full=Protein deacetylase HDAC6 {ECO:0000305}; EC=3.5.1.-
{ECO:0000269|PubMed:26080397, ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:30770470,
ECO:0000269|PubMed:31857589}; AltName: Full=E3 ubiquitin-protein ligase HDAC6
{ECO:0000305}; EC=2.3.2.- {ECO:0000269|PubMed:24882211}; AltName: Full=Tubulin-lysine
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Synonyms=KIAA0901 {ECO:0000303|PubMed:10048485}; ORFNames=JM21;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the histone deacetylase family. HD type 2
protein_domains: HDAC_PDAC. (IPR050284); His_deacetylse. (IPR000286); His_deacetylse_dom.
(IPR023801); His_deacetylse_dom_sf. (IPR037138); Ureohydrolase_dom_sf. (IPR023696)
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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: Q9UBN7
Protein Description: RecName: Full=Protein deacetylase HDAC6 {ECO:0000305}; EC=3.5.1.- {ECO:0000269|PubMed:26080397, ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:30770470, ECO:0000269|PubMed:31857589}; AltName: Full=E3 ubiquitin-protein ligase HDAC6 {ECO:0000305}; EC=2.3.2.- {ECO:0000269|PubMed:24882211}; AltName: Full=Tubulin-lysine deacetylase HDAC6 {ECO:0000305}; EC=3.5.1.- {ECO:0000269|PubMed:12024216, ECO:0000269|PubMed:20308065};
Gene Information: Name=HDAC6 {ECO:0000303|PubMed:10220385, ECO:0000312|HGNC:HGNC:14064}; Synonyms=KIAA0901 {ECO:0000303|PubMed:10048485}; ORFNames=JM21;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the histone deacetylase family. HD type 2
Key Domains: HDAC_PDAC. (IPR050284); His_deacetylse. (IPR000286); His_deacetylse_dom. (IPR023801); His_deacetylse_dom_sf. (IPR037138); Ureohydrolase_dom_sf. (IPR023696)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HDAC6" 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 'HDAC6' 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 HDAC6 (gene ID: HDAC6, UniProt: Q9UBN7) 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: Q9UBN7
Protein Description: RecName: Full=Protein deacetylase HDAC6 {ECO:0000305}; EC=3.5.1.- {ECO:0000269|PubMed:26080397, ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:30770470, ECO:0000269|PubMed:31857589}; AltName: Full=E3 ubiquitin-protein ligase HDAC6 {ECO:0000305}; EC=2.3.2.- {ECO:0000269|PubMed:24882211}; AltName: Full=Tubulin-lysine deacetylase HDAC6 {ECO:0000305}; EC=3.5.1.- {ECO:0000269|PubMed:12024216, ECO:0000269|PubMed:20308065};
Gene Information: Name=HDAC6 {ECO:0000303|PubMed:10220385, ECO:0000312|HGNC:HGNC:14064}; Synonyms=KIAA0901 {ECO:0000303|PubMed:10048485}; ORFNames=JM21;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the histone deacetylase family. HD type 2
Key Domains: HDAC_PDAC. (IPR050284); His_deacetylse. (IPR000286); His_deacetylse_dom. (IPR023801); His_deacetylse_dom_sf. (IPR037138); Ureohydrolase_dom_sf. (IPR023696)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HDAC6" 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 HDAC6 (gene ID: HDAC6, UniProt: Q9UBN7) 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 HDAC6 (UniProt Q9UBN7)

Identity verification and nomenclature
- Gene/protein identity: HDAC6 is a human class IIb histone deacetylase with two Zn2+-dependent catalytic deacetylase domains (variously termed CD1/DD1 and CD2/DD2), an internal SE14 serine–glutamate repeat region that drives cytoplasmic retention, and a C‑terminal ZnF‑UBP (BUZ) domain that binds unanchored and K63-linked ubiquitin. It possesses NLS/NES signals enabling nuclear–cytoplasmic shuttling, but resides predominantly in the cytoplasm. These features match the UniProt Q9UBN7 annotation and distinguish HDAC6 from other HDAC isoforms (class IIb versus IIa/I) (https://doi.org/10.3390/ph17050620; https://doi.org/10.1111/cbdd.14366; https://doi.org/10.3389/fimmu.2023.1216548) (curcio2024thehistonedeacetylase pages 4-6, han2024discussiononstructure pages 7-7, qu2023histonedeacetylase6’s pages 2-4).

Key concepts, enzymatic function, and substrates
- Reaction and specificity: HDAC6 is a Zn2+-dependent lysine deacetylase (EC 3.5.1.-) that primarily targets non-histone substrates in the cytoplasm, most notably α-tubulin at K40, HSP90 (e.g., K294), and cortactin. Deacetylation of α-tubulin regulates microtubule stability and transport; deacetylation of HSP90 modulates chaperone function; deacetylation of cortactin affects actin dynamics and invasion. Additional reported substrates include Ku70, Tau, β‑catenin, survivin, and peroxiredoxins, supporting broad roles in cytoskeleton and stress responses (https://doi.org/10.3390/ph17050620; https://doi.org/10.1111/cbdd.14366; https://doi.org/10.3390/ijms26031274) (curcio2024thehistonedeacetylase pages 4-6, han2024discussiononstructure pages 7-7, asaad2025regulationofhdac6 pages 2-4).
- Localization and domains: HDAC6 is mainly cytoplasmic due to SE14‑mediated retention and NES/NLS‑regulated shuttling; domains DD1/DD2 confer deacetylase activity; ZnF‑UBP enables ubiquitin binding; a dynein-motor binding region mediates cargo transport along microtubules to the MTOC (https://doi.org/10.3389/fimmu.2023.1216548; https://doi.org/10.3390/biomedicines12112631) (qu2023histonedeacetylase6’s pages 2-4, spallotta2024theroleof pages 14-15).

Pathways and cellular roles
- Cytoskeleton and proteostasis: HDAC6 is a central coordinator of microtubule dynamics and proteostasis. Through ZnF‑UBP and dynein interactions it binds ubiquitinated aggregates and directs them to the MTOC for aggresome formation and autophagic clearance; it regulates HSP90/HSF1 chaperone responses and interacts with the inflammasome machinery (https://doi.org/10.3390/biomedicines12112631) (spallotta2024theroleof pages 14-15).
- Innate immunity and antiviral signaling: HDAC6 intersects with RIG‑I and cGAS–STING pathways, modulating type I interferon responses. Recent work highlights viral strategies to subvert HDAC6: SARS‑CoV‑2 nucleocapsid (N) protein engages and upregulates HDAC6 to promote replication; swine enteric coronaviruses cleave HDAC6 via nsp5 to blunt its antiviral functions. Reviews synthesize HDAC6’s positive and negative regulatory roles in IFN signaling depending on context (https://doi.org/10.1186/s12985-024-02460-5; https://doi.org/10.1128/jvi.01814-23; https://doi.org/10.3389/fimmu.2023.1216548) (mukherjee2024sarscov2nucleocapsidprotein pages 7-10, spallotta2024theroleof pages 18-20, qu2023histonedeacetylase6’s pages 2-4).

Recent developments (prioritizing 2023–2024)
- Structural/chemical biology: Difluoromethyl-1,3,4-oxadiazoles were reported as slow‑binding substrate-analog inhibitors with unprecedented HDAC6 isoform selectivity, offering a non-hydroxamate avenue with favorable kinetics (Journal of Biological Chemistry, 2023; https://doi.org/10.1016/j.jbc.2022.102800) (curcio2024thehistonedeacetylase pages 4-6).
- Antiviral interface: Primary studies in 2024 showed SARS‑CoV‑2 N protein drives HDAC6 accumulation and interaction with stress granule proteins, facilitating replication, and that multiple swine coronaviruses deploy nsp5 to cleave HDAC6 and disable its deacetylase-mediated antiviral actions (Virology Journal 2024, https://doi.org/10.1186/s12985-024-02460-5; Journal of Virology 2024, https://doi.org/10.1128/jvi.01814-23) (mukherjee2024sarscov2nucleocapsidprotein pages 7-10, spallotta2024theroleof pages 18-20).
- PROTACs and target engagement: Reviews and methodological advances in 2024–2025 detail rapid growth of HDAC6-targeted PROTAC degraders and the emergence of live-cell target engagement/degradation assays, enabling systematic evaluation and potentially improved pharmacology compared with occupancy-based inhibition (Theranostics 2024, https://doi.org/10.7150/thno.92526) (spallotta2024theroleof pages 18-20).

Current applications and implementations
- Selective HDAC6 inhibitors in the clinic: Ricolinostat (ACY‑1215) and Citarinostat (ACY‑241) have been tested in Phase 1/2 settings. In a Phase Ib/II lymphoma cohort, ricolinostat showed a highly favorable safety profile with predominantly grade 1–2 AEs (diarrhea 57%, nausea 57%, fatigue 43%); no dose‑limiting toxicities were observed. Objective responses were not seen; stable disease occurred in 50% of evaluable patients with median PFS of 56 days (The Oncologist, 2021; https://doi.org/10.1002/onco.13673) (amengual2021firstinclassselectivehdac6 pages 4-5).
- Representative trials and statuses with URLs:
• NCT02091063 (Ricolinostat in relapsed/refractory lymphoid malignancies): Status TERMINATED (lack of funding); start 2014; completion 2019; sponsor Columbia University. Record: https://clinicaltrials.gov/ct2/show/NCT02091063 (NCT02091063).
• NCT01323751 (Ricolinostat ± bortezomib and dexamethasone in multiple myeloma): Status COMPLETED; enrollment 120. Record: https://clinicaltrials.gov/ct2/show/NCT01323751 (NCT02551185).
• NCT02632071 (Ricolinostat + nab‑paclitaxel in metastatic breast cancer): Status COMPLETED; enrollment 17. Record: https://clinicaltrials.gov/ct2/show/NCT02632071 (NCT02551185).
• NCT02551185 (Citarinostat + paclitaxel in advanced solid tumors): Status COMPLETED; enrollment 20; start 2015-12-22; completion 2019-10-04; last update 2020-02-26. Record: https://clinicaltrials.gov/ct2/show/NCT02551185 (NCT02551185).
• NCT02635061 (Citarinostat + nivolumab in unresectable NSCLC): Status TERMINATED; enrollment 17. Record: https://clinicaltrials.gov/ct2/show/NCT02635061 (NCT02551185).
- Translational areas: Oncology (myeloma, lymphomas, and exploratory solid tumors), neurology/neurodegeneration (HDAC6’s cytoskeletal/proteostasis roles), and infectious disease/immunology (context‑dependent modulation of interferon responses and viral restriction) are active domains for HDAC6 targeting (https://doi.org/10.3390/biomedicines12112631; https://doi.org/10.3389/fimmu.2023.1216548) (spallotta2024theroleof pages 14-15, qu2023histonedeacetylase6’s pages 2-4).

Expert opinions and analysis
- Synthesis from recent reviews positions HDAC6 as a multifunctional, predominantly cytoplasmic deacetylase that couples cytoskeletal regulation to protein quality control and innate immunity. Domain architecture (DD1/DD2, SE14, ZnF‑UBP) underlies its ability to bind ubiquitin, recruit dynein, and direct aggresome-autophagy processes, while substrate scope (α‑tubulin, HSP90, cortactin) explains effects on transport, chaperoning, and motility. The 2023–2024 literature highlights a nuanced role in antiviral signaling—supporting or restraining IFN pathways depending on context—and documents viral countermeasures that target HDAC6 directly (https://doi.org/10.3389/fimmu.2023.1216548; https://doi.org/10.1186/s12985-024-02460-5; https://doi.org/10.1128/jvi.01814-23) (qu2023histonedeacetylase6’s pages 2-4, mukherjee2024sarscov2nucleocapsidprotein pages 7-10, spallotta2024theroleof pages 18-20).

Recent statistics and data
- Clinical safety/efficacy: In relapsed/refractory lymphoma treated with ricolinostat 160 mg BID or QD, grade 1–2 AEs predominated (diarrhea 57%, nausea 57%, fatigue 43%); grade 3–4 anemia and hypercalcemia occurred in 9.5% each; 50% stable disease; median PFS 56 days; study stopped early (https://doi.org/10.1002/onco.13673) (amengual2021firstinclassselectivehdac6 pages 4-5).
- Trial-level metadata: ACY‑241 + paclitaxel (NCT02551185) completed with 20 participants; ACY‑1215 studies show mixed statuses (completed/terminated) across myeloma, lymphoma, breast cancer; specific NCT statuses and dates are listed above from ClinicalTrials.gov records (NCT02551185, NCT02091063).

Embedded summary table
| Category | Details | Key sources (DOI / URL) |
|---|---|---|
| Identity / Domains | Class IIb HDAC; two Zn2+-dependent catalytic domains (DD1/CD1 & DD2/CD2); SE14 serine–glutamate repeat (cytoplasmic retention); C‑terminal ZnF‑UBP (ubiquitin‑binding zinc finger); NLS/NES motifs for shuttling | Curcio et al. 2024 https://doi.org/10.3390/ph17050620; Han et al. 2024 https://doi.org/10.1111/cbdd.14366 (curcio2024thehistonedeacetylase pages 4-6, han2024discussiononstructure pages 7-7, qu2023histonedeacetylase6’s pages 2-4) |
| Principal substrates | α‑tubulin (K40); HSP90 (reported K site e.g., K294); cortactin; additional reported deacetylation targets: Ku70, Tau, β‑catenin | Curcio et al. 2024 https://doi.org/10.3390/ph17050620; Asaad et al. 2025 https://doi.org/10.3390/ijms26031274; Spallotta & Illi 2024 https://doi.org/10.3390/biomedicines12112631 (curcio2024thehistonedeacetylase pages 4-6, asaad2025regulationofhdac6 pages 2-4, spallotta2024theroleof pages 14-15) |
| Cellular localization | Predominantly cytoplasmic with nucleo‑cytoplasmic shuttling (NLS/NES); SE14 mediates cytoplasmic retention | Qu et al. 2023 https://doi.org/10.3389/fimmu.2023.1216548; Han et al. 2024 https://doi.org/10.1111/cbdd.14366; Curcio et al. 2024 https://doi.org/10.3390/ph17050620 (qu2023histonedeacetylase6’s pages 2-4, han2024discussiononstructure pages 7-7, curcio2024thehistonedeacetylase pages 4-6) |
| Core pathways / roles | Regulation of microtubule dynamics and cell motility; aggresome formation and autophagy via ubiquitin binding (ZnF‑UBP + dynein transport to MTOC); proteostasis and chaperone regulation (HSP90/HSF1); modulation of innate immunity (RIG‑I, cGAS–STING / IFN pathways) | Spallotta & Illi 2024 https://doi.org/10.3390/biomedicines12112631; Qu et al. 2023 https://doi.org/10.3389/fimmu.2023.1216548; Mukherjee et al. 2024 https://doi.org/10.1186/s12985-024-02460-5 (spallotta2024theroleof pages 14-15, qu2023histonedeacetylase6’s pages 2-4, mukherjee2024sarscov2nucleocapsidprotein pages 7-10) |
| Key 2023–2024 developments | Antiviral biology: SARS‑CoV‑2 N protein engages/upregulates HDAC6 (proviral interactions) and swine enteric CoVs cleave HDAC6 (nsp5) to blunt antiviral activity; medicinal chemistry: slow‑binding difluoromethyl‑1,3,4‑oxadiazoles (JBC 2023) with high HDAC6 selectivity; rapid growth of HDAC6 PROTAC degraders and target‑engagement assays | Mukherjee et al. 2024 https://doi.org/10.1186/s12985-024-02460-5; Li et al. 2024 https://doi.org/10.1128/jvi.01814-23; Cellupica et al. 2023 JBC https://doi.org/10.1016/j.jbc.2022.102800; reviews on PROTACs/HDAC6 degraders (Theranostics 2024) (mukherjee2024sarscov2nucleocapsidprotein pages 7-10, spallotta2024theroleof pages 18-20, qu2023histonedeacetylase6’s pages 2-4) |
| Applications / Clinical | Selective HDAC6 inhibitors (ricolinostat / ACY‑1215; citarinostat / ACY‑241) show acceptable tolerability and disease‑stabilization signals in combinations; representative trials: NCT02091063 (ricolinostat; terminated), NCT01323751 (ricolinostat + bortezomib; completed), NCT02551185 (citarinostat + paclitaxel; completed) | Amengual et al. 2021 Oncologist https://doi.org/10.1002/onco.13673; ClinicalTrials.gov NCT02091063 https://clinicaltrials.gov/ct2/show/NCT02091063 (amengual2021firstinclassselectivehdac6 pages 4-5, NCT02091063); NCT01323751, NCT02551185 (NCT02551185) |

Table: Compact, cited summary of human HDAC6 (UniProt Q9UBN7) domains, substrates, localization, functions, 2023–2024 developments, and representative clinical trials; useful for quick reference and citation.

Conclusion
Human HDAC6 (UniProt Q9UBN7) is a class IIb deacetylase whose unique domain composition (DD1/DD2, SE14, ZnF‑UBP) enables cytoplasmic deacetylation of non‑histone substrates (α‑tubulin, HSP90, cortactin) and coupling of cytoskeletal regulation with proteostasis and innate immunity. 2023–2024 studies emphasize its context‑dependent influence on antiviral signaling and document viral strategies that antagonize HDAC6. In the clinic, selective HDAC6 inhibition remains well tolerated but has shown modest single‑agent efficacy; rational combinations and next‑generation chemotypes (slow‑binding selective inhibitors, PROTAC degraders) are active directions. Together, these insights delineate HDAC6’s primary biochemical functions, cellular locales, and translational potential, grounded in recent peer‑reviewed literature and clinical records (curcio2024thehistonedeacetylase pages 4-6, han2024discussiononstructure pages 7-7, qu2023histonedeacetylase6’s pages 2-4, asaad2025regulationofhdac6 pages 2-4, spallotta2024theroleof pages 14-15, mukherjee2024sarscov2nucleocapsidprotein pages 7-10, spallotta2024theroleof pages 18-20, amengual2021firstinclassselectivehdac6 pages 4-5, NCT02551185, NCT02091063).

References

(curcio2024thehistonedeacetylase pages 4-6): Antonio Curcio, Roberta Rocca, Stefano Alcaro, and Anna Artese. The histone deacetylase family: structural features and application of combined computational methods. Pharmaceuticals, 17:620, May 2024. URL: https://doi.org/10.3390/ph17050620, doi:10.3390/ph17050620. This article has 49 citations and is from a poor quality or predatory journal.
(han2024discussiononstructure pages 7-7): Han Han, Xue Feng, Ting He, Yingfan Wu, Tianmei He, Ziwen Yue, and Weiqiang Zhou. Discussion on structure classification and regulation function of histone deacetylase and their inhibitor. Chemical Biology & Drug Design, Sep 2024. URL: https://doi.org/10.1111/cbdd.14366, doi:10.1111/cbdd.14366. This article has 26 citations and is from a peer-reviewed journal.
(qu2023histonedeacetylase6’s pages 2-4): Min Qu, Huijun Zhang, Pengyuan Cheng, Ashenafi Kiros Wubshet, Xiangping Yin, Xiangwei Wang, and Yuefeng Sun. Histone deacetylase 6’s function in viral infection, innate immunity, and disease: latest advances. Frontiers in Immunology, Aug 2023. URL: https://doi.org/10.3389/fimmu.2023.1216548, doi:10.3389/fimmu.2023.1216548. This article has 24 citations and is from a peer-reviewed journal.
(asaad2025regulationofhdac6 pages 2-4): Leen Asaad, Benjamin Pepperrell, Emma McErlean, and Fiona Furlong. Regulation of hdac6 catalytic activity in cancer: the role of post-translational modifications and protein–protein interactions. International Journal of Molecular Sciences, 26:1274, Feb 2025. URL: https://doi.org/10.3390/ijms26031274, doi:10.3390/ijms26031274. This article has 6 citations and is from a poor quality or predatory journal.
(spallotta2024theroleof pages 14-15): Francesco Spallotta and Barbara Illi. The role of hdac6 in glioblastoma multiforme: a new avenue to therapeutic interventions? Biomedicines, 12:2631, Nov 2024. URL: https://doi.org/10.3390/biomedicines12112631, doi:10.3390/biomedicines12112631. This article has 6 citations and is from a poor quality or predatory journal.
(mukherjee2024sarscov2nucleocapsidprotein pages 7-10): Arpita Mukherjee, Mahadeb Lo, Pritam Chandra, Ratul Datta Chaudhuri, Papiya De, Shanta Dutta, and Mamta Chawla-Sarkar. Sars-cov-2 nucleocapsid protein promotes self-deacetylation by inducing hdac6 to facilitate viral replication. Virology Journal, Aug 2024. URL: https://doi.org/10.1186/s12985-024-02460-5, doi:10.1186/s12985-024-02460-5. This article has 5 citations and is from a peer-reviewed journal.
(spallotta2024theroleof pages 18-20): Francesco Spallotta and Barbara Illi. The role of hdac6 in glioblastoma multiforme: a new avenue to therapeutic interventions? Biomedicines, 12:2631, Nov 2024. URL: https://doi.org/10.3390/biomedicines12112631, doi:10.3390/biomedicines12112631. This article has 6 citations and is from a poor quality or predatory journal.
(amengual2021firstinclassselectivehdac6 pages 4-5): Jennifer E. Amengual, Jennifer K. Lue, Helen Ma, Renee Lichtenstein, Bijal Shah, Serge Cremers, Simon Jones, and Ahmed Sawas. First-in-class selective hdac6 inhibitor (acy-1215) has a highly favorable safety profile in patients with relapsed and refractory lymphoma. The Oncologist, 26:184-e366, Feb 2021. URL: https://doi.org/10.1002/onco.13673, doi:10.1002/onco.13673. This article has 56 citations.
(NCT02091063): Jennifer Amengual. ACY-1215 for Relapsed/Refractory Lymphoid Malignancies. Jennifer Amengual. 2014. ClinicalTrials.gov Identifier: NCT02091063
(NCT02551185): ACY 241 in Combination With Paclitaxel in Patients With Advanced Solid Tumors. Celgene. 2015. ClinicalTrials.gov Identifier: NCT02551185

Citations

spallotta2024theroleof pages 14-15
curcio2024thehistonedeacetylase pages 4-6
spallotta2024theroleof pages 18-20
han2024discussiononstructure pages 7-7
https://doi.org/10.3390/ph17050620;
https://doi.org/10.1111/cbdd.14366;
https://doi.org/10.3389/fimmu.2023.1216548
https://doi.org/10.3390/ijms26031274
https://doi.org/10.3389/fimmu.2023.1216548;
https://doi.org/10.3390/biomedicines12112631
https://doi.org/10.1186/s12985-024-02460-5;
https://doi.org/10.1128/jvi.01814-23;
https://doi.org/10.1016/j.jbc.2022.102800
https://doi.org/10.1128/jvi.01814-23
https://doi.org/10.7150/thno.92526
https://doi.org/10.1002/onco.13673
https://clinicaltrials.gov/ct2/show/NCT02091063
https://clinicaltrials.gov/ct2/show/NCT01323751
https://clinicaltrials.gov/ct2/show/NCT02632071
https://clinicaltrials.gov/ct2/show/NCT02551185
https://clinicaltrials.gov/ct2/show/NCT02635061
https://doi.org/10.3390/biomedicines12112631;
https://doi.org/10.1111/cbdd.14366
https://doi.org/10.3390/ijms26031274;
https://doi.org/10.3390/ph17050620
https://doi.org/10.1186/s12985-024-02460-5
https://doi.org/10.1016/j.jbc.2022.102800;
https://doi.org/10.1002/onco.13673;
https://doi.org/10.3390/ph17050620,
https://doi.org/10.1111/cbdd.14366,
https://doi.org/10.3389/fimmu.2023.1216548,
https://doi.org/10.3390/ijms26031274,
https://doi.org/10.3390/biomedicines12112631,
https://doi.org/10.1186/s12985-024-02460-5,
https://doi.org/10.1002/onco.13673,

📄 View Raw YAML

id: Q9UBN7
gene_symbol: HDAC6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: HDAC6 is a class IIb cytoplasmic protein deacetylase with unique 
  dual catalytic domains (CD1/CD2) and a C-terminal ZnF-UBP ubiquitin-binding 
  domain. It primarily deacetylates non-histone substrates in the cytoplasm, 
  most notably alpha-tubulin (K40), HSP90, and cortactin. HDAC6 plays a central 
  role in microtubule-dependent cell motility, cilium disassembly, and the 
  aggresome-autophagy pathway for clearing misfolded protein aggregates. The 
  SE14 repeat region mediates cytoplasmic retention, while the ZnF-UBP domain 
  enables binding to polyubiquitinated misfolded proteins and their transport 
  via dynein motors to aggresomes for autophagic clearance.
existing_annotations:
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HDAC6 is predominantly cytoplasmic, where it associates with 
        microtubules and carries out its primary deacetylase functions on 
        tubulin, HSP90, and cortactin [PMID:12024216]. The SE14 repeat region 
        mediates cytoplasmic retention.
      action: ACCEPT
      reason: Core localization. HDAC6 is established as a predominantly 
        cytoplasmic deacetylase, distinct from nuclear HDACs. This is supported 
        by extensive experimental evidence [PMID:12024216, UniProt Q9UBN7].
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is localized exclusively in the cytoplasm, 
            where it associates with microtubules
        - reference_id: file:human/HDAC6/HDAC6-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0019213
      label: deacetylase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HDAC6 is a Zn2+-dependent deacetylase with two catalytic domains.
        It deacetylates non-histone substrates including alpha-tubulin, HSP90, 
        cortactin, peroxiredoxins, and other proteins.
      action: ACCEPT
      reason: Core molecular function. HDAC6 is a bona fide protein deacetylase.
        The term is appropriately general as a parent term to more specific 
        deacetylase activities.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6, functions as a tubulin deacetylase
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HDAC6 localizes to the cytosol where it carries out its 
        deacetylase functions.
      action: ACCEPT
      reason: Core localization. Cytosol is an appropriate more specific term 
        than cytoplasm. HDAC6 is found in the soluble cytosolic fraction as well
        as associated with microtubules.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is localized exclusively in the cytoplasm
  - term:
      id: GO:0090042
      label: tubulin deacetylation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HDAC6 deacetylates alpha-tubulin at K40, regulating microtubule 
        stability and dynamics. This is one of the primary functions of HDAC6 
        [PMID:12024216].
      action: ACCEPT
      reason: Core biological process. Tubulin deacetylation is one of the 
        best-characterized and most important functions of HDAC6. Multiple 
        studies demonstrate this activity both in vitro and in vivo.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: In vivo, the overexpression of HDAC6 leads to a 
            global deacetylation of alpha-tubulin, whereas a decrease in HDAC6 
            increases alpha-tubulin acetylation. In vitro, purified HDAC6 
            potently deacetylates alpha-tubulin in assembled microtubules.
  - term:
      id: GO:1904115
      label: axon cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: HDAC6 localizes to axons and regulates axonal transport via 
        tubulin deacetylation.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 does localize to axons (by sequence similarity), this 
        is a specialized neuronal localization rather than a core function 
        across all cell types. Its axonal role relates to regulating microtubule
        dynamics and transport.
  - term:
      id: GO:0000118
      label: histone deacetylase complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 can interact with other HDACs (e.g., HDAC11) but primarily 
        functions as a cytoplasmic non-histone deacetylase, not as part of 
        classical histone deacetylase complexes.
      action: MARK_AS_OVER_ANNOTATED
      reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone 
        substrates. While it can interact with other HDACs, it does not 
        primarily function in canonical nuclear histone deacetylase complexes. 
        This annotation may be misleading about HDAC6's actual role.
  - term:
      id: GO:0003779
      label: actin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: HDAC6 interacts with cortactin (an actin-binding protein) and 
        F-actin. It deacetylates cortactin to regulate actin dynamics.
      action: KEEP_AS_NON_CORE
      reason: HDAC6 does interact with actin cytoskeleton components, but the 
        primary functional relationship is through cortactin deacetylation 
        rather than direct actin binding as a core function.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 can shuttle to the nucleus under certain conditions (valine
        deprivation, DNA damage, differentiation) but is predominantly 
        cytoplasmic.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 can translocate to the nucleus, its primary 
        localization and function is cytoplasmic. Nuclear localization is 
        context-dependent and represents a specialized rather than core 
        localization.
      supported_by:
        - reference_id: UniProt:Q9UBN7
          supporting_text: Can shuttle between the cytoplasm and the nucleus 
            (PubMed:39567688). Retained in the cytoplasm by binding to valine 
            via the primate-specific SE14 repeat region
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation for cytoplasm localization.
      action: ACCEPT
      reason: Core localization. Same as IBA annotation - HDAC6 is predominantly
        cytoplasmic.
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: HDAC6 localizes to the centrosome where it participates in cilium
        disassembly.
      action: ACCEPT
      reason: Core localization for cilium-related function. HDAC6 localizes to 
        the centrosome/ ciliary basal body and is required for cilium 
        disassembly via deacetylation of alpha-tubulin [PMID:17604723, 
        PMID:26246421].
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: interactions between the prometastatic scaffolding 
            protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at
            the basal body of cilia causes phosphorylation and activation of 
            HDAC6, a tubulin deacetylase, promoting ciliary disassembly
  - term:
      id: GO:0005856
      label: cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: HDAC6 associates with the cytoskeleton, particularly 
        microtubules.
      action: ACCEPT
      reason: Core localization. HDAC6 associates with microtubules and the 
        cytoskeleton as part of its role in regulating microtubule dynamics.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is localized exclusively in the cytoplasm, 
            where it associates with microtubules
  - term:
      id: GO:0005929
      label: cilium
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: HDAC6 localizes to cilia where it promotes ciliary disassembly 
        via tubulin deacetylation.
      action: ACCEPT
      reason: HDAC6 localizes to cilia/ciliary basal body and has a direct role 
        in cilium disassembly through deacetylation of alpha-tubulin 
        [PMID:17604723].
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: Aurora A (AurA) kinase at the basal body of cilia 
            causes phosphorylation and activation of HDAC6, a tubulin 
            deacetylase, promoting ciliary disassembly
  - term:
      id: GO:0006325
      label: chromatin organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Despite being named a histone deacetylase, HDAC6 primarily 
        functions on non-histone substrates in the cytoplasm.
      action: MARK_AS_OVER_ANNOTATED
      reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone 
        substrates. Its role in chromatin organization is minimal compared to 
        nuclear HDACs. UniProt explicitly notes it was "originally thought to be
        a histone deacetylase" but subsequent work showed it primarily 
        deacetylates non-histone substrates.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: HDAC6 plays a genuine role in autophagy, particularly aggrephagy.
        It binds polyubiquitinated misfolded proteins via its ZnF-UBP domain and
        transports them to aggresomes for autophagic clearance [PMID:14675537, 
        PMID:16192271].
      action: ACCEPT
      reason: Core function. HDAC6's role in autophagy/aggrephagy is 
        well-established and represents a key non-deacetylase function mediated 
        by its ZnF-UBP domain and dynein binding.
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors, thereby acting to recruit 
            misfolded protein cargo to dynein motors for transport to aggresomes
        - reference_id: PMID:16192271
          supporting_text: HDAC6-dependent retrograde transport on microtubules 
            is used by cells to increase the efficiency and selectivity of 
            autophagic degradation
  - term:
      id: GO:0006950
      label: response to stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 participates in cellular stress responses, particularly 
        misfolded protein stress and heat stress responses.
      action: KEEP_AS_NON_CORE
      reason: HDAC6 does participate in stress responses (misfolded protein 
        stress, heat shock response), but this is a very broad term. The 
        specific mechanisms (aggresome formation, HSP90 regulation) are more 
        informative annotations.
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 is a Zn2+-dependent deacetylase that binds 3 Zn2+ ions per 
        subunit.
      action: ACCEPT
      reason: Core molecular function. Zinc binding is essential for HDAC6's 
        deacetylase activity and for the ZnF-UBP domain function.
      supported_by:
        - reference_id: UniProt:Q9UBN7
          supporting_text: Binds 3 Zn(2+) ions per subunit
  - term:
      id: GO:0016236
      label: macroautophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 regulates macroautophagy through multiple mechanisms 
        including aggresome formation and cortactin deacetylation promoting 
        autophagosome-lysosome fusion.
      action: ACCEPT
      reason: Core function. HDAC6's role in autophagy is well-established 
        through its aggresome function and regulation of autophagosome-lysosome 
        fusion.
      supported_by:
        - reference_id: PMID:16192271
          supporting_text: HDAC6 and microtubules are required for autophagic 
            degradation of aggregated huntingtin
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: HDAC6 has E3 ubiquitin-protein ligase activity (transferase 
        activity transferring ubiquitin), in addition to its deacetylase 
        function.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 does have ubiquitin ligase activity (mediates 
        ubiquitination of MSH2), this is a more specialized function. The term 
        is very broad and the more specific ubiquitin protein ligase activity 
        term is more informative.
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: HDAC6 is a hydrolase that cleaves acetyl groups from lysine 
        residues.
      action: ACCEPT
      reason: Core molecular function. Deacetylation is a hydrolysis reaction, 
        so this parent term is accurate though very general.
  - term:
      id: GO:0030424
      label: axon
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 localizes to axons where it regulates microtubule dynamics 
        and axonal transport.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization. While HDAC6 is present in 
        axons, this is cell-type specific rather than a core localization across
        all cell types.
  - term:
      id: GO:0030425
      label: dendrite
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 localizes to dendrites in neurons.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization rather than core localization.
  - term:
      id: GO:0032886
      label: regulation of microtubule-based process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 regulates microtubule-based processes through deacetylation
        of alpha-tubulin, affecting microtubule stability, dynamics, and 
        dependent processes.
      action: ACCEPT
      reason: Core function. This accurately captures HDAC6's role in regulating
        microtubule dynamics through tubulin deacetylation.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: overexpression of HDAC6 promotes chemotactic cell 
            movement, supporting the idea that HDAC6-mediated deacetylation 
            regulates microtubule-dependent cell motility
  - term:
      id: GO:0043204
      label: perikaryon
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 localizes to the perikaryon (cell body) of neurons.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization rather than core localization 
        across all cell types.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: HDAC6 binds zinc ions which are required for its deacetylase 
        activity.
      action: ACCEPT
      reason: Core molecular function. Metal (zinc) binding is essential for 
        HDAC6 catalytic activity.
  - term:
      id: GO:0051129
      label: negative regulation of cellular component organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 can negatively regulate cellular component organization 
        through effects on microtubule stability and cilium disassembly.
      action: KEEP_AS_NON_CORE
      reason: Very broad term. The specific effects (microtubule dynamics, 
        cilium disassembly) are more informative annotations.
  - term:
      id: GO:0051130
      label: positive regulation of cellular component organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 can positively regulate cellular component organization 
        through aggresome formation.
      action: KEEP_AS_NON_CORE
      reason: Very broad term. More specific terms like aggresome assembly are 
        more informative.
  - term:
      id: GO:0098732
      label: macromolecule deacylation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 catalyzes deacetylation (a type of deacylation) of 
        proteins.
      action: ACCEPT
      reason: Core function. Deacetylation is the primary enzymatic activity of 
        HDAC6.
  - term:
      id: GO:0120025
      label: plasma membrane bounded cell projection
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: HDAC6 localizes to cell projections including cilia, axons, and 
        dendrites.
      action: KEEP_AS_NON_CORE
      reason: Very broad parent term. More specific terms (cilium, axon, 
        dendrite) are more informative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12024216
    review:
      summary: Generic protein binding annotation from the study that identified
        HDAC6 as a tubulin deacetylase.
      action: MODIFY
      reason: '''Protein binding'' is uninformative. This study showed HDAC6 binds
        tubulin, which should be captured by more specific terms like alpha-tubulin
        binding or microtubule binding.'
      proposed_replacement_terms:
        - id: GO:0043014
          label: alpha-tubulin binding
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is a microtubule-associated deacetylase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12354939
    review:
      summary: This study showed HDAC6 binds polyubiquitin through its zinc 
        finger (PAZ/BUZ) domain.
      action: MODIFY
      reason: '''Protein binding'' is uninformative. This study demonstrated ubiquitin
        binding which is captured by GO:0043130 (ubiquitin binding).'
      proposed_replacement_terms:
        - id: GO:0043130
          label: ubiquitin binding
      supported_by:
        - reference_id: PMID:12354939
          supporting_text: Histone deacetylase 6 binds polyubiquitin through its
            zinc finger (PAZ domain) and copurifies with deubiquitinating 
            enzymes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16919237
    review:
      summary: Study showing HDAC6 interaction (via HSP90 pathway).
      action: MODIFY
      reason: '''Protein binding'' is uninformative. Should be captured by more specific
        binding terms.'
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:16919237
          supporting_text: Breast cancer metastasis suppressor 1 (BRMS1) is 
            stabilized by the Hsp90 chaperone.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18356165
    review:
      summary: Study showing HDAC6 interactions with beta-catenin and EGFR 
        pathway components.
      action: MODIFY
      reason: '''Protein binding'' is uninformative. More specific terms available.'
      proposed_replacement_terms:
        - id: GO:0008013
          label: beta-catenin binding
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19036992
    review:
      summary: Study showing direct binding of HDAC6 with parkin at the 
        centrosome.
      action: KEEP_AS_NON_CORE
      reason: While 'protein binding' is uninformative, the parkin interaction 
        relates to HDAC6's role in the autophagy/mitophagy pathway.
      supported_by:
        - reference_id: PMID:19036992
          supporting_text: Direct binding with histone deacetylase 6 mediates 
            the reversible recruitment of parkin to the centrosome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19167333
    review:
      summary: Study on centrosomal Cdc20-APC pathway in dendrite morphogenesis.
      action: KEEP_AS_NON_CORE
      reason: Interaction related to neuronal development, not core HDAC6 
        function.
      supported_by:
        - reference_id: PMID:19167333
          supporting_text: A centrosomal Cdc20-APC pathway controls dendrite 
            morphogenesis in postmitotic neurons.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19893491
    review:
      summary: Study showing CYLD negatively regulates HDAC6 and tubulin 
        acetylation.
      action: KEEP_AS_NON_CORE
      reason: CYLD-HDAC6 interaction is a regulatory mechanism, not a core 
        function.
      supported_by:
        - reference_id: PMID:19893491
          supporting_text: CYLD negatively regulates cell-cycle progression by 
            inactivating HDAC6 and increasing the levels of acetylated tubulin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20029029
    review:
      summary: Study on HDAC6 regulation of EGFR trafficking.
      action: KEEP_AS_NON_CORE
      reason: EGFR interaction may be indirect through HDAC6's effects on 
        microtubule dynamics.
      supported_by:
        - reference_id: PMID:20029029
          supporting_text: Regulation of epidermal growth factor receptor 
            trafficking by lysine deacetylase HDAC6.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21220424
    review:
      summary: Study on HDAC6 regulation of HIV Tat acetylation.
      action: KEEP_AS_NON_CORE
      reason: Viral protein interaction, specialized context.
      supported_by:
        - reference_id: PMID:21220424
          supporting_text: 2011 Jan 10. Regulation of Tat acetylation and 
            transactivation activity by the microtubule-associated deacetylase 
            HDAC6.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21532619
    review:
      summary: Study showing HTLV-1 Tax protein interacts with HDAC6.
      action: KEEP_AS_NON_CORE
      reason: Viral protein interaction, specialized context.
      supported_by:
        - reference_id: PMID:21532619
          supporting_text: The HTLV-1 Tax protein inhibits formation of stress 
            granules by interacting with histone deacetylase 6.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21847094
    review:
      summary: Study showing HDAC6 deacetylates cortactin affecting 
        angiogenesis.
      action: MODIFY
      reason: '''Protein binding'' is uninformative. Cortactin is a known HDAC6 substrate.'
      proposed_replacement_terms:
        - id: GO:0003779
          label: actin binding
      supported_by:
        - reference_id: PMID:21847094
          supporting_text: Class IIb HDAC6 regulates endothelial cell migration 
            and angiogenesis by deacetylation of cortactin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21952047
    review:
      summary: Study on PKC alpha regulation of interferon induction via HDAC6.
      action: KEEP_AS_NON_CORE
      reason: Signaling pathway interaction, downstream effect.
      supported_by:
        - reference_id: PMID:21952047
          supporting_text: PKC alpha regulates Sendai virus-mediated interferon 
            induction through HDAC6 and β-catenin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22193721
    review:
      summary: Study showing GRK2/HDAC6 interaction modulates cell spreading and
        motility.
      action: KEEP_AS_NON_CORE
      reason: Regulatory interaction affecting cell motility.
      supported_by:
        - reference_id: PMID:22193721
          supporting_text: A novel GRK2/HDAC6 interaction modulates cell 
            spreading and motility.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22645275
    review:
      summary: Study on ATP13A2 interactors including HDAC6 in alpha-synuclein 
        misfolding.
      action: KEEP_AS_NON_CORE
      reason: Interaction relevant to protein quality control pathway.
      supported_by:
        - reference_id: PMID:22645275
          supporting_text: May 29. Identification of novel ATP13A2 interactors 
            and their role in α-synuclein misfolding and toxicity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23084749
    review:
      summary: Study on HDAC6 regulation of CD133 and beta-catenin signaling.
      action: KEEP_AS_NON_CORE
      reason: Cancer signaling context, downstream effect.
      supported_by:
        - reference_id: PMID:23084749
          supporting_text: 2012 Oct 19. Regulation of CD133 by HDAC6 promotes 
            β-catenin signaling to suppress cancer cell differentiation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24658140
    review:
      summary: Mammalian membrane two-hybrid assay identifying protein 
        interactions.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interaction data, context unclear.
      supported_by:
        - reference_id: PMID:24658140
          supporting_text: The mammalian-membrane two-hybrid assay (MaMTH) for 
            probing membrane-protein interactions in human cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29281743
    review:
      summary: Study on HDAC6 in innate immune and autophagy responses to 
        Listeria infection.
      action: KEEP_AS_NON_CORE
      reason: Infection context, relates to autophagy function.
      supported_by:
        - reference_id: PMID:29281743
          supporting_text: eCollection 2017 Dec.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31980649
    review:
      summary: Large-scale interactome study in EGFR network.
      action: KEEP_AS_NON_CORE
      reason: High-throughput data, not specific to core function.
      supported_by:
        - reference_id: PMID:31980649
          supporting_text: Extensive rewiring of the EGFR network in colorectal 
            cancer cells expressing transforming levels of KRAS(G13D).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: Interactome mapping of neurodegenerative disease proteins.
      action: KEEP_AS_NON_CORE
      reason: High-throughput data related to protein aggregation.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Dual proteome-scale interactome study.
      action: KEEP_AS_NON_CORE
      reason: High-throughput data, not specific to core function.
      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:0000153
      label: cytoplasmic ubiquitin ligase complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 has E3 ubiquitin ligase activity and can ubiquitinate 
        substrates like MSH2.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 has ubiquitin ligase activity, this is not its primary
        function. The deacetylase activity is the core function.
  - term:
      id: GO:0004407
      label: histone deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 was originally named for histone deacetylase activity but 
        primarily deacetylates non-histone cytoplasmic substrates.
      action: MARK_AS_OVER_ANNOTATED
      reason: UniProt explicitly notes that HDAC6 "was originally thought to be 
        a histone deacetylase. However, subsequent work has shown that it is 
        predominantly cytoplasmic and deacetylates a range of non-histone 
        substrates." The more appropriate term is protein lysine deacetylase 
        activity.
      proposed_replacement_terms:
        - id: GO:0033558
          label: protein lysine deacetylase activity
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Duplicate cytosol annotation.
      action: ACCEPT
      reason: Core localization, consistent with other cytosol annotations.
  - term:
      id: GO:0008017
      label: microtubule binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 associates with microtubules where it deacetylates 
        alpha-tubulin.
      action: ACCEPT
      reason: Core molecular function. HDAC6 binds microtubules as part of its 
        tubulin deacetylase function [PMID:12024216].
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is localized exclusively in the cytoplasm, 
            where it associates with microtubules
  - term:
      id: GO:0015630
      label: microtubule cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 localizes to the microtubule cytoskeleton.
      action: ACCEPT
      reason: Core localization. HDAC6 associates with microtubules 
        [PMID:12024216].
  - term:
      id: GO:0031648
      label: protein destabilization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 can promote protein destabilization through deacetylation 
        and ubiquitination.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of HDAC6 activity on specific substrates (e.g., 
        MSH2).
  - term:
      id: GO:0032461
      label: positive regulation of protein oligomerization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 can affect protein oligomerization through its deacetylase 
        activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect, context-specific (e.g., tau aggregation).
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Very generic term indicating HDAC6 is part of protein complexes.
      action: ACCEPT
      reason: True but very general. HDAC6 participates in multiple protein 
        complexes.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 is a protein lysine deacetylase that removes acetyl groups 
        from lysine residues of non-histone substrates.
      action: ACCEPT
      reason: Core molecular function. This is the most accurate term for 
        HDAC6's primary enzymatic activity.
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 deacetylates alpha-tubulin at K40.
      action: ACCEPT
      reason: Core molecular function [PMID:12024216].
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6, functions as a tubulin deacetylase
  - term:
      id: GO:0043005
      label: neuron projection
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 localizes to neuron projections (axons, dendrites).
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization.
  - term:
      id: GO:0043130
      label: ubiquitin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 binds ubiquitin via its C-terminal ZnF-UBP domain.
      action: ACCEPT
      reason: Core molecular function. The ZnF-UBP domain binds 
        polyubiquitinated proteins and is essential for HDAC6's role in 
        aggresome formation [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors
  - term:
      id: GO:0044297
      label: cell body
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 localizes to the cell body.
      action: KEEP_AS_NON_CORE
      reason: Very general localization term.
  - term:
      id: GO:0048156
      label: tau protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 interacts with tau protein. Tau can inhibit HDAC6 
        deacetylase activity [PMID:19457097].
      action: KEEP_AS_NON_CORE
      reason: Tau is a regulatory interactor of HDAC6 rather than a core 
        functional binding partner.
      supported_by:
        - reference_id: PMID:19457097
          supporting_text: tau binds to the tubulin-deacetylase, histone 
            deacetylase 6 (HDAC6), decreasing its activity with a consequent 
            increase in tubulin acetylation
  - term:
      id: GO:0048487
      label: beta-tubulin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 binds tubulin including beta-tubulin as part of microtubule
        binding.
      action: KEEP_AS_NON_CORE
      reason: The primary substrate is alpha-tubulin K40. Beta-tubulin binding 
        is likely incidental to microtubule association.
  - term:
      id: GO:0051646
      label: mitochondrion localization
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: HDAC6 can affect mitochondrial localization/transport through its
        effects on microtubule dynamics and axonal transport.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of HDAC6's role in microtubule regulation rather
        than direct mitochondrial localization function.
  - term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 has E3 ubiquitin ligase activity mediated by its histone 
        deacetylase domain 1.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 does have ubiquitin ligase activity (for MSH2), this 
        is a secondary function. The deacetylase activity is the primary 
        enzymatic function.
  - term:
      id: GO:1905091
      label: positive regulation of type 2 mitophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: HDAC6 participates in parkin-mediated mitophagy through its 
        ubiquitin-binding function.
      action: KEEP_AS_NON_CORE
      reason: Specialized autophagy function related to HDAC6's broader role in 
        aggrephagy/autophagy.
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HDAC6 localizes to the centrosome based on immunofluorescence 
        data.
      action: ACCEPT
      reason: Core localization for cilium-related function [PMID:26246421].
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HDAC6 localizes to cytosol based on immunofluorescence data.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0036064
      label: ciliary basal body
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HDAC6 localizes to the ciliary basal body based on 
        immunofluorescence data.
      action: ACCEPT
      reason: Core localization for cilium disassembly function [PMID:17604723, 
        PMID:26246421].
  - term:
      id: GO:0034605
      label: cellular response to heat
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371511
    review:
      summary: HDAC6 participates in heat shock response through HSF1 activation
        pathway.
      action: KEEP_AS_NON_CORE
      reason: HDAC6's role in heat shock response is related to its HSP90 
        deacetylation function. The heat shock response is a downstream process.
  - term:
      id: GO:0060271
      label: cilium assembly
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5620920
    review:
      summary: HDAC6 affects cilium assembly through its role in cilium 
        disassembly via tubulin deacetylation.
      action: MODIFY
      reason: HDAC6 promotes cilium DISassembly rather than assembly. The term 
        should be cilium disassembly.
      proposed_replacement_terms:
        - id: GO:0061523
          label: cilium disassembly
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:19457097
    review:
      summary: Study showing tau inhibits HDAC6 tubulin deacetylase activity.
      action: ACCEPT
      reason: Core molecular function. Supports HDAC6's role as a tubulin 
        deacetylase.
      supported_by:
        - reference_id: PMID:19457097
          supporting_text: tau binds to the tubulin-deacetylase, histone 
            deacetylase 6 (HDAC6), decreasing its activity
  - term:
      id: GO:0060632
      label: regulation of microtubule-based movement
    evidence_type: IDA
    original_reference_id: PMID:19228685
    review:
      summary: HDAC6 regulates microtubule-based movement through tubulin 
        deacetylation.
      action: ACCEPT
      reason: Core function directly related to tubulin deacetylation.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:18356165
    review:
      summary: HDAC6 participates in EGFR signaling.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect, not a core function of HDAC6.
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0010727
      label: negative regulation of hydrogen peroxide metabolic process
    evidence_type: IMP
    original_reference_id: PMID:18606987
    review:
      summary: HDAC6 deacetylates peroxiredoxins, affecting their H2O2 reducing 
        activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of peroxiredoxin deacetylation rather than core 
        function.
      supported_by:
        - reference_id: PMID:18606987
          supporting_text: HDAC6 is a specific deacetylase of peroxiredoxins and
            is involved in redox regulation
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:19228685
    review:
      summary: HDAC6 binds enzymes including farnesyltransferase.
      action: KEEP_AS_NON_CORE
      reason: Generic binding term, context-specific regulatory interaction.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0033148
      label: positive regulation of intracellular estrogen receptor signaling 
        pathway
    evidence_type: IMP
    original_reference_id: PMID:18316616
    review:
      summary: HDAC6 affects estrogen receptor signaling.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect through HSP90 deacetylation or other 
        mechanisms.
      supported_by:
        - reference_id: PMID:18316616
          supporting_text: Selective inhibition of histone deacetylase 2 
            silences progesterone receptor-mediated signaling.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:18356165
    review:
      summary: Experimental evidence for protein lysine deacetylase activity.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: TAS
    original_reference_id: PMID:28386764
    review:
      summary: Review article supporting protein lysine deacetylase activity.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:28386764
          supporting_text: Epub 2017 Apr 6. Roles of tau protein in health and 
            disease.
  - term:
      id: GO:0036479
      label: peroxidase inhibitor activity
    evidence_type: IMP
    original_reference_id: PMID:18606987
    review:
      summary: HDAC6 deacetylates peroxiredoxins, decreasing their peroxidase 
        activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of peroxiredoxin deacetylation. HDAC6 is not 
        itself an inhibitor but deacetylates peroxiredoxins which modulates 
        their activity.
      supported_by:
        - reference_id: PMID:18606987
          supporting_text: Acetylation of Prx increases its reducing activity...
            Thus, HDAC6 and Prx are targets for modulating intracellular redox 
            status
  - term:
      id: GO:0042030
      label: ATPase inhibitor activity
    evidence_type: IMP
    original_reference_id: PMID:15916966
    review:
      summary: HDAC6 deacetylates HSP90, affecting its ATPase-dependent 
        chaperone activity.
      action: KEEP_AS_NON_CORE
      reason: Indirect effect through HSP90 deacetylation. HDAC6 modulates HSP90
        function but is not itself an ATPase inhibitor.
      supported_by:
        - reference_id: PMID:15916966
          supporting_text: HDAC6 functions as an Hsp90 deacetylase. Inactivation
            of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an 
            essential cochaperone, p23, and a loss of chaperone activity
  - term:
      id: GO:0032461
      label: positive regulation of protein oligomerization
    evidence_type: IMP
    original_reference_id: PMID:23962722
    review:
      summary: HDAC6 affects tau aggregation/oligomerization through 
        deacetylation of KXGS motifs.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect on tau aggregation in neurodegeneration.
      supported_by:
        - reference_id: PMID:23962722
          supporting_text: Acetylation of the KXGS motifs in tau is a critical 
            determinant in modulation of tau aggregation and clearance.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:23962722
    review:
      summary: HDAC6 deacetylates tau protein at KXGS motifs.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:23962722
          supporting_text: Acetylation of the KXGS motifs in tau is a critical 
            determinant in modulation of tau aggregation and clearance.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:31857589
    review:
      summary: HDAC6 deacetylates p62/SQSTM1.
      action: ACCEPT
      reason: Core molecular function. Demonstrates HDAC6 deacetylates p62 which
        regulates autophagy.
      supported_by:
        - reference_id: PMID:31857589
          supporting_text: Requirement for p62 acetylation in the aggregation of
            ubiquitylated proteins under nutrient stress.
  - term:
      id: GO:1905336
      label: negative regulation of aggrephagy
    evidence_type: IDA
    original_reference_id: PMID:31857589
    review:
      summary: HDAC6 deacetylation of p62 regulates aggrephagy.
      action: MODIFY
      reason: HDAC6 actually promotes aggrephagy through aggresome formation. 
        The p62 deacetylation may have complex regulatory effects but HDAC6's 
        overall role is to promote aggrephagy.
      proposed_replacement_terms:
        - id: GO:1905335
          label: positive regulation of aggrephagy
      supported_by:
        - reference_id: PMID:31857589
          supporting_text: Requirement for p62 acetylation in the aggregation of
            ubiquitylated proteins under nutrient stress.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:26246421
    review:
      summary: Direct experimental evidence for cytoplasmic localization.
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:26246421
          supporting_text: Deacetylation of α-tubulin and cortactin is required 
            for HDAC6 to trigger ciliary disassembly.
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: PMID:26246421
    review:
      summary: Direct experimental evidence for centrosome localization.
      action: ACCEPT
      reason: Core localization for cilium function.
      supported_by:
        - reference_id: PMID:26246421
          supporting_text: Deacetylation of α-tubulin and cortactin is required 
            for HDAC6 to trigger ciliary disassembly.
  - term:
      id: GO:0036064
      label: ciliary basal body
    evidence_type: IDA
    original_reference_id: PMID:26246421
    review:
      summary: Direct experimental evidence for ciliary basal body localization.
      action: ACCEPT
      reason: Core localization for cilium disassembly function.
      supported_by:
        - reference_id: PMID:26246421
          supporting_text: Deacetylation of α-tubulin and cortactin is required 
            for HDAC6 to trigger ciliary disassembly.
  - term:
      id: GO:0061523
      label: cilium disassembly
    evidence_type: IDA
    original_reference_id: PMID:26246421
    review:
      summary: HDAC6 promotes cilium disassembly via deacetylation of 
        alpha-tubulin and cortactin.
      action: ACCEPT
      reason: Core biological process. HDAC6-mediated tubulin deacetylation is 
        required for cilium disassembly [PMID:17604723, PMID:26246421].
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: phosphorylation and activation of HDAC6, a tubulin 
            deacetylase, promoting ciliary disassembly
        - reference_id: PMID:26246421
          supporting_text: Deacetylation of α-tubulin and cortactin is required 
            for HDAC6 to trigger ciliary disassembly.
  - term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
    evidence_type: IMP
    original_reference_id: PMID:24413532
    review:
      summary: HDAC6 involved in MTA1-mediated epigenetic regulation of ESR1.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect in breast cancer, not a core function.
      supported_by:
        - reference_id: PMID:24413532
          supporting_text: 2014 Jan 10. Differential regulation of estrogen 
            receptor α expression in breast cancer cells by 
            metastasis-associated protein 1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17604723
    review:
      summary: HDAC6 interacts with Aurora A and HEF1 at the ciliary basal body.
      action: MODIFY
      reason: '''Protein binding'' is uninformative. The specific interaction with
        Aurora A kinase is more informative.'
      proposed_replacement_terms:
        - id: GO:0051219
          label: phosphoprotein binding
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: HEF1-dependent Aurora A activation induces 
            disassembly of the primary cilium.
  - term:
      id: GO:0036064
      label: ciliary basal body
    evidence_type: IDA
    original_reference_id: PMID:17604723
    review:
      summary: HDAC6 localizes to ciliary basal body.
      action: ACCEPT
      reason: Core localization for cilium function [PMID:17604723].
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: Aurora A (AurA) kinase at the basal body of cilia 
            causes phosphorylation and activation of HDAC6
  - term:
      id: GO:0061523
      label: cilium disassembly
    evidence_type: IMP
    original_reference_id: PMID:17604723
    review:
      summary: HDAC6 is required for cilium disassembly.
      action: ACCEPT
      reason: Core biological process [PMID:17604723].
      supported_by:
        - reference_id: PMID:17604723
          supporting_text: this pathway is both necessary and sufficient for 
            ciliary resorption
  - term:
      id: GO:0051787
      label: misfolded protein binding
    evidence_type: EXP
    original_reference_id: PMID:17785525
    review:
      summary: HDAC6 binds misfolded proteins through its ZnF-UBP domain 
        recognizing polyubiquitin chains.
      action: ACCEPT
      reason: Core molecular function. Essential for HDAC6's role in aggresome 
        formation [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors
        - reference_id: PMID:17785525
          supporting_text: HDAC6 controls major cell response pathways to 
            cytotoxic accumulation of protein aggregates.
  - term:
      id: GO:0019896
      label: axonal transport of mitochondrion
    evidence_type: IGI
    original_reference_id: PMID:28105056
    review:
      summary: HDAC6 affects axonal mitochondrial transport through effects on 
        microtubule acetylation.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal function related to microtubule regulation.
      supported_by:
        - reference_id: PMID:28105056
          supporting_text: HDAC6 Inhibitors Rescued the Defective Axonal 
            Mitochondrial Movement in Motor Neurons Derived from the Induced 
            Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 
            Mutation.
  - term:
      id: GO:0001222
      label: transcription corepressor binding
    evidence_type: IPI
    original_reference_id: PMID:12535528
    review:
      summary: HDAC6 interacts with LCoR transcription corepressor.
      action: KEEP_AS_NON_CORE
      reason: Context-specific interaction in transcriptional regulation, not a 
        core function.
      supported_by:
        - reference_id: PMID:12535528
          supporting_text: Ligand-dependent nuclear receptor corepressor LCoR 
            functions by histone deacetylase-dependent and -independent 
            mechanisms.
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: EXP
    original_reference_id: PMID:12024216
    review:
      summary: Original discovery of HDAC6 as a tubulin deacetylase.
      action: ACCEPT
      reason: Core molecular function. This is the seminal paper establishing 
        HDAC6 as the tubulin deacetylase.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6, functions as a tubulin deacetylase... In 
            vitro, purified HDAC6 potently deacetylates alpha-tubulin in 
            assembled microtubules
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20308065
    review:
      summary: HDAC6 interacts with TPPP/p25 which inhibits its tubulin 
        deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: '''Protein binding'' is uninformative. TPPP is a regulatory interactor.'
      supported_by:
        - reference_id: PMID:20308065
          supporting_text: 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by
            inhibiting histone deacetylase 6.
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:20308065
    review:
      summary: Direct demonstration of HDAC6 tubulin deacetylase activity.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:20308065
          supporting_text: 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by
            inhibiting histone deacetylase 6.
  - term:
      id: GO:0090042
      label: tubulin deacetylation
    evidence_type: IDA
    original_reference_id: PMID:20308065
    review:
      summary: Direct demonstration of HDAC6-mediated tubulin deacetylation.
      action: ACCEPT
      reason: Core biological process.
      supported_by:
        - reference_id: PMID:20308065
          supporting_text: 2010 Mar 22. TPPP/p25 promotes tubulin acetylation by
            inhibiting histone deacetylase 6.
  - term:
      id: GO:0090042
      label: tubulin deacetylation
    evidence_type: IDA
    original_reference_id: PMID:23093407
    review:
      summary: ROCK signaling pathway regulates HDAC6-mediated tubulin 
        deacetylation.
      action: ACCEPT
      reason: Core biological process.
      supported_by:
        - reference_id: PMID:23093407
          supporting_text: 2012 Oct 23. Rho-associated coiled-coil kinase (ROCK)
            protein controls microtubule dynamics in a novel signaling pathway 
            that regulates cell migration.
  - term:
      id: GO:0031333
      label: negative regulation of protein-containing complex assembly
    evidence_type: IMP
    original_reference_id: PMID:23962722
    review:
      summary: HDAC6 affects protein complex assembly through deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect, likely related to tau aggregation 
        studies.
      supported_by:
        - reference_id: PMID:23962722
          supporting_text: Acetylation of the KXGS motifs in tau is a critical 
            determinant in modulation of tau aggregation and clearance.
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IDA
    original_reference_id: PMID:28516954
    review:
      summary: 'Note: PMID:28516954 is about HDAC10, not HDAC6. This may be an error.'
      action: UNDECIDED
      reason: Need to verify this annotation - the PMID is about HDAC10 
        structure and polyamine deacetylation, which may have been mis-annotated
        to HDAC6.
      supported_by:
        - reference_id: PMID:28516954
          supporting_text: Histone deacetylase 10 structure and molecular 
            function as a polyamine deacetylase.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:28516954
    review:
      summary: 'Note: PMID:28516954 is about HDAC10, not HDAC6.'
      action: UNDECIDED
      reason: Need to verify - may be annotation error as this paper is about 
        HDAC10.
      supported_by:
        - reference_id: PMID:28516954
          supporting_text: Histone deacetylase 10 structure and molecular 
            function as a polyamine deacetylase.
  - term:
      id: GO:0047611
      label: acetylspermidine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:28516954
    negated: true
    review:
      summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 
        does NOT have acetylspermidine deacetylase activity - this activity is 
        specific to HDAC10.
      action: ACCEPT
      reason: This is correctly a NOT annotation. The paper PMID:28516954 
        established that polyamine deacetylation is a function of HDAC10, not 
        HDAC6. The negative annotation correctly reflects that HDAC6 lacks this 
        activity.
      supported_by:
        - reference_id: PMID:28516954
          supporting_text: Histone deacetylase 10 structure and molecular 
            function as a polyamine deacetylase.
  - term:
      id: GO:0106047
      label: polyamine deacetylation
    evidence_type: IDA
    original_reference_id: PMID:28516954
    negated: true
    review:
      summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 
        is NOT involved in polyamine deacetylation - this activity is specific 
        to HDAC10.
      action: ACCEPT
      reason: This is correctly a NOT annotation. The paper PMID:28516954 
        established that polyamine deacetylation is a function of HDAC10, not 
        HDAC6.
      supported_by:
        - reference_id: PMID:28516954
          supporting_text: Histone deacetylase 10 structure and molecular 
            function as a polyamine deacetylase.
  - term:
      id: GO:0106048
      label: spermidine deacetylation
    evidence_type: IDA
    original_reference_id: PMID:28516954
    negated: true
    review:
      summary: This is a NOT annotation. PMID:28516954 demonstrated that HDAC6 
        is NOT involved in spermidine deacetylation - this activity is specific 
        to HDAC10.
      action: ACCEPT
      reason: This is correctly a NOT annotation. The paper PMID:28516954 
        established that spermidine deacetylation is a function of HDAC10, not 
        HDAC6.
      supported_by:
        - reference_id: PMID:28516954
          supporting_text: Histone deacetylase 10 structure and molecular 
            function as a polyamine deacetylase.
  - term:
      id: GO:0048156
      label: tau protein binding
    evidence_type: NAS
    original_reference_id: PMID:28386764
    review:
      summary: Review article discussing tau-HDAC6 interaction.
      action: KEEP_AS_NON_CORE
      reason: Tau is a regulatory interactor rather than core functional 
        partner.
      supported_by:
        - reference_id: PMID:28386764
          supporting_text: Epub 2017 Apr 6. Roles of tau protein in health and 
            disease.
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IDA
    original_reference_id: PMID:24413532
    review:
      summary: HDAC6 involvement in transcriptional regulation of ESR1.
      action: MARK_AS_OVER_ANNOTATED
      reason: HDAC6 is primarily a cytoplasmic deacetylase. Direct DNA binding 
        is not a core function. This may reflect an indirect effect or 
        context-specific nuclear function.
      supported_by:
        - reference_id: PMID:24413532
          supporting_text: 2014 Jan 10. Differential regulation of estrogen 
            receptor α expression in breast cancer cells by 
            metastasis-associated protein 1.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: TAS
    original_reference_id: PMID:19457097
    review:
      summary: Cytoplasmic localization noted in tau-HDAC6 interaction study.
      action: ACCEPT
      reason: Core localization. HDAC6 is well-established as a cytoplasmic 
        protein.
      supported_by:
        - reference_id: PMID:19457097
          supporting_text: Epub 2009 May 7. Tau--an inhibitor of deacetylase 
            HDAC6 function.
  - term:
      id: GO:0016235
      label: aggresome
    evidence_type: TAS
    original_reference_id: PMID:19457097
    review:
      summary: HDAC6 localizes to aggresomes.
      action: ACCEPT
      reason: Core localization. HDAC6 is a component of the aggresome 
        [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6, a microtubule-associated deacetylase, is a 
            component of the aggresome
        - reference_id: PMID:19457097
          supporting_text: Epub 2009 May 7. Tau--an inhibitor of deacetylase 
            HDAC6 function.
  - term:
      id: GO:0048156
      label: tau protein binding
    evidence_type: ISS
    original_reference_id: PMID:19457097
    review:
      summary: Tau binds and inhibits HDAC6.
      action: KEEP_AS_NON_CORE
      reason: Tau is a regulatory interactor.
      supported_by:
        - reference_id: PMID:19457097
          supporting_text: tau binds to the tubulin-deacetylase, histone 
            deacetylase 6 (HDAC6), decreasing its activity
  - term:
      id: GO:0048156
      label: tau protein binding
    evidence_type: TAS
    original_reference_id: PMID:19457097
    review:
      summary: Tau binds HDAC6.
      action: KEEP_AS_NON_CORE
      reason: Duplicate - tau is a regulatory interactor.
      supported_by:
        - reference_id: PMID:19457097
          supporting_text: Epub 2009 May 7. Tau--an inhibitor of deacetylase 
            HDAC6 function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25422469
    review:
      summary: HDAC6 interacts with UBD/FAT10.
      action: KEEP_AS_NON_CORE
      reason: UBD is a ubiquitin-like modifier; interaction related to ubiquitin
        binding function.
      supported_by:
        - reference_id: PMID:25422469
          supporting_text: Disruption of FAT10-MAD2 binding inhibits tumor 
            progression.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24687993
    review:
      summary: HDAC6 interacts with FAM65B and dysferlin during myogenesis.
      action: KEEP_AS_NON_CORE
      reason: Context-specific interaction during myogenic differentiation.
      supported_by:
        - reference_id: PMID:24687993
          supporting_text: Fam65b is important for formation of the 
            HDAC6-dysferlin protein complex during myogenic cell 
            differentiation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27556504
    review:
      summary: FAM65B interaction with HDAC6 in T cell proliferation.
      action: KEEP_AS_NON_CORE
      reason: Context-specific interaction in immune cells.
      supported_by:
        - reference_id: PMID:27556504
          supporting_text: FAM65B controls the proliferation of transformed and 
            primary T cells.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:24687993
    review:
      summary: Cytoplasmic localization during myogenic differentiation.
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:24687993
          supporting_text: Fam65b is important for formation of the 
            HDAC6-dysferlin protein complex during myogenic cell 
            differentiation.
  - term:
      id: GO:0016241
      label: regulation of macroautophagy
    evidence_type: IMP
    original_reference_id: PMID:16192271
    review:
      summary: HDAC6 regulates macroautophagy of aggregated proteins.
      action: ACCEPT
      reason: Core function. HDAC6 is required for autophagic degradation of 
        aggregated proteins [PMID:16192271].
      supported_by:
        - reference_id: PMID:16192271
          supporting_text: HDAC6-dependent retrograde transport on microtubules 
            is used by cells to increase the efficiency and selectivity of 
            autophagic degradation
  - term:
      id: GO:0061734
      label: type 2 mitophagy
    evidence_type: IGI
    original_reference_id: PMID:20457763
    review:
      summary: HDAC6 participates in parkin-mediated mitophagy.
      action: KEEP_AS_NON_CORE
      reason: Specialized autophagy function related to parkin pathway.
      supported_by:
        - reference_id: PMID:20457763
          supporting_text: May 10. Disease-causing mutations in parkin impair 
            mitochondrial ubiquitination, aggregation, and HDAC6-dependent 
            mitophagy.
  - term:
      id: GO:0005771
      label: multivesicular body
    evidence_type: TAS
    original_reference_id: PMID:25548531
    review:
      summary: HDAC6 involved in autophagy-related membrane trafficking.
      action: KEEP_AS_NON_CORE
      reason: Related to autophagy function but not core localization.
      supported_by:
        - reference_id: PMID:25548531
          supporting_text: 'Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in
            Autophagy.'
  - term:
      id: GO:0010506
      label: regulation of autophagy
    evidence_type: TAS
    original_reference_id: PMID:25548531
    review:
      summary: HDAC6 regulates autophagy.
      action: ACCEPT
      reason: Core function - autophagy regulation is a key HDAC6 function.
      supported_by:
        - reference_id: PMID:25548531
          supporting_text: 'Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in
            Autophagy.'
  - term:
      id: GO:1903146
      label: regulation of autophagy of mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:25548531
    review:
      summary: HDAC6 involved in mitophagy regulation.
      action: KEEP_AS_NON_CORE
      reason: Specialized autophagy function.
      supported_by:
        - reference_id: PMID:25548531
          supporting_text: 'Dec 12. ATP13A2 and Alpha-synuclein: a Metal Taste in
            Autophagy.'
  - term:
      id: GO:0031647
      label: regulation of protein stability
    evidence_type: IMP
    original_reference_id: PMID:23580651
    review:
      summary: HDAC6 regulates mutant SOD1 aggregation through tubulin 
        acetylation.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect in neurodegeneration models.
      supported_by:
        - reference_id: PMID:23580651
          supporting_text: 2013 Apr 11. HDAC6 regulates mutant SOD1 aggregation 
            through two SMIR motifs and tubulin acetylation.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:21753002
    review:
      summary: HDAC6 interacts with Ambra1 and ubiquitin ligases in mitophagy.
      action: KEEP_AS_NON_CORE
      reason: Interaction related to autophagy pathway.
      supported_by:
        - reference_id: PMID:21753002
          supporting_text: Parkin interacts with Ambra1 to induce mitophagy.
  - term:
      id: GO:0030424
      label: axon
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: HDAC6 localizes to axons based on sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization.
  - term:
      id: GO:0030425
      label: dendrite
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: HDAC6 localizes to dendrites based on sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization.
  - term:
      id: GO:0043204
      label: perikaryon
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: HDAC6 localizes to perikaryon based on sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: Specialized neuronal localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5324632
    review:
      summary: Cytosol localization in HSF1 activation pathway.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5618331
    review:
      summary: Cytosol localization in microtubule deacetylation pathway.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9646348
    review:
      summary: Cytosol localization in aggrephagy pathway.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9646679
    review:
      summary: Cytosol localization in aggresome formation pathway.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9646685
    review:
      summary: Cytosol localization in aggresome pathway.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0004407
      label: histone deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:23322205
    review:
      summary: Study testing HDAC6 inhibitors.
      action: MODIFY
      reason: HDAC6 is more accurately described as a protein lysine 
        deacetylase. It primarily deacetylates non-histone substrates.
      proposed_replacement_terms:
        - id: GO:0033558
          label: protein lysine deacetylase activity
      supported_by:
        - reference_id: PMID:23322205
          supporting_text: Jan 15. A novel small molecule hydroxamate 
            preferentially inhibits HDAC6 activity and tumour growth.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17872950
    review:
      summary: HDAC6 interacts with CHOP/DDIT3.
      action: KEEP_AS_NON_CORE
      reason: Context-specific interaction in ER stress response.
      supported_by:
        - reference_id: PMID:17872950
          supporting_text: 2007 Sep 14. Critical and functional regulation of 
            CHOP (C/EBP homologous protein) through the N-terminal portion.
  - term:
      id: GO:0035967
      label: cellular response to topologically incorrect protein
    evidence_type: IMP
    original_reference_id: PMID:16192271
    review:
      summary: HDAC6 mediates response to misfolded proteins by facilitating 
        aggresome formation.
      action: ACCEPT
      reason: Core function. HDAC6 is essential for cellular response to 
        misfolded protein accumulation [PMID:14675537, PMID:16192271].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: cells deficient in HDAC6 fail to clear misfolded 
            protein aggregates from the cytoplasm, cannot form aggresomes 
            properly, and are hypersensitive to the accumulation of misfolded 
            proteins
        - reference_id: PMID:16192271
          supporting_text: 2005 Sep 28. HDAC6 and microtubules are required for 
            autophagic degradation of aggregated huntingtin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19081074
    review:
      summary: HDAC6 interacts with BBIP1, a BBSome subunit, affecting 
        ciliogenesis.
      action: KEEP_AS_NON_CORE
      reason: Interaction related to cilium function.
      supported_by:
        - reference_id: PMID:19081074
          supporting_text: A BBSome subunit links ciliogenesis, microtubule 
            stability, and acetylation.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Nuclear localization based on sequence similarity.
      action: KEEP_AS_NON_CORE
      reason: HDAC6 is predominantly cytoplasmic but can shuttle to nucleus 
        under specific conditions.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Cytosol localization based on sequence similarity.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0008017
      label: microtubule binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Microtubule binding based on sequence similarity.
      action: ACCEPT
      reason: Core molecular function.
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Tubulin deacetylase activity based on sequence similarity.
      action: ACCEPT
      reason: Core molecular function.
  - term:
      id: GO:0090042
      label: tubulin deacetylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Tubulin deacetylation based on sequence similarity.
      action: ACCEPT
      reason: Core biological process.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19033385
    review:
      summary: HDAC6 interacts with FAT10/UBD under proteasome inhibition.
      action: KEEP_AS_NON_CORE
      reason: Interaction related to ubiquitin-like modifier system.
      supported_by:
        - reference_id: PMID:19033385
          supporting_text: Nov 25. The ubiquitin-like modifier FAT10 interacts 
            with HDAC6 and localizes to aggresomes under proteasome inhibition.
  - term:
      id: GO:0004407
      label: histone deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:10220385
    review:
      summary: Original identification of HDAC6 as a histone deacetylase family 
        member.
      action: MODIFY
      reason: While HDAC6 was originally identified as an HDAC, subsequent work 
        has shown it primarily deacetylates non-histone substrates. Should be 
        protein lysine deacetylase activity.
      proposed_replacement_terms:
        - id: GO:0033558
          label: protein lysine deacetylase activity
      supported_by:
        - reference_id: PMID:10220385
          supporting_text: Three proteins define a class of human histone 
            deacetylases related to yeast Hda1p.
  - term:
      id: GO:0070840
      label: dynein complex binding
    evidence_type: IDA
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 binds dynein motors to transport misfolded proteins to 
        aggresomes.
      action: ACCEPT
      reason: Core molecular function. Dynein binding is essential for HDAC6's 
        role in aggresome formation [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors, thereby acting to recruit 
            misfolded protein cargo to dynein motors for transport to aggresomes
  - term:
      id: GO:0070842
      label: aggresome assembly
    evidence_type: IMP
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 is required for aggresome assembly.
      action: ACCEPT
      reason: Core biological process [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: cells deficient in HDAC6 fail to clear misfolded 
            protein aggregates from the cytoplasm, cannot form aggresomes 
            properly
  - term:
      id: GO:0070845
      label: polyubiquitinated misfolded protein transport
    evidence_type: IMP
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 mediates transport of polyubiquitinated misfolded proteins 
        to aggresomes.
      action: ACCEPT
      reason: Core biological process [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors, thereby acting to recruit 
            misfolded protein cargo to dynein motors for transport to aggresomes
  - term:
      id: GO:0006515
      label: protein quality control for misfolded or incompletely synthesized 
        proteins
    evidence_type: IMP
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 is essential for cellular protein quality control by 
        facilitating aggresome formation and autophagic clearance of misfolded 
        proteins.
      action: ACCEPT
      reason: Core biological process [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: These findings identify HDAC6 as a crucial player in 
            the cellular management of misfolded protein-induced stress
  - term:
      id: GO:0016235
      label: aggresome
    evidence_type: IDA
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 localizes to aggresomes.
      action: ACCEPT
      reason: Core localization [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6, a microtubule-associated deacetylase, is a 
            component of the aggresome
  - term:
      id: GO:0031593
      label: polyubiquitin modification-dependent protein binding
    evidence_type: IDA
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 binds polyubiquitinated proteins via its ZnF-UBP domain.
      action: ACCEPT
      reason: Core molecular function [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: HDAC6 has the capacity to bind both polyubiquitinated
            misfolded proteins and dynein motors
  - term:
      id: GO:0048156
      label: tau protein binding
    evidence_type: IDA
    original_reference_id: PMID:18636984
    review:
      summary: HDAC6 binds tau protein.
      action: KEEP_AS_NON_CORE
      reason: Tau is a regulatory interactor.
      supported_by:
        - reference_id: PMID:18636984
          supporting_text: Epub 2008 Jul 12. Histone deacetylase 6 interacts 
            with the microtubule-associated protein tau.
  - term:
      id: GO:0051788
      label: response to misfolded protein
    evidence_type: IMP
    original_reference_id: PMID:14675537
    review:
      summary: HDAC6 mediates cellular response to misfolded proteins.
      action: ACCEPT
      reason: Core biological process [PMID:14675537].
      supported_by:
        - reference_id: PMID:14675537
          supporting_text: These findings identify HDAC6 as a crucial player in 
            the cellular management of misfolded protein-induced stress
  - term:
      id: GO:0060765
      label: regulation of androgen receptor signaling pathway
    evidence_type: TAS
    original_reference_id: PMID:18852123
    review:
      summary: HDAC6 affects androgen receptor signaling through HSP90.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of HSP90 deacetylation.
      supported_by:
        - reference_id: PMID:18852123
          supporting_text: Genistein down-regulates androgen receptor by 
            modulating HDAC6-Hsp90 chaperone function.
  - term:
      id: GO:0006886
      label: intracellular protein transport
    evidence_type: IMP
    original_reference_id: PMID:16192271
    review:
      summary: HDAC6 involved in transport of aggregated proteins via 
        microtubules.
      action: ACCEPT
      reason: Core function - HDAC6 mediates retrograde transport of misfolded 
        proteins to aggresomes [PMID:14675537, PMID:16192271].
      supported_by:
        - reference_id: PMID:16192271
          supporting_text: HDAC6-dependent retrograde transport on microtubules 
            is used by cells to increase the efficiency and selectivity of 
            autophagic degradation
  - term:
      id: GO:0016234
      label: inclusion body
    evidence_type: IDA
    original_reference_id: PMID:16192271
    review:
      summary: HDAC6 localizes to inclusion bodies/aggresomes.
      action: ACCEPT
      reason: Core localization related to aggresome function.
      supported_by:
        - reference_id: PMID:16192271
          supporting_text: 2005 Sep 28. HDAC6 and microtubules are required for 
            autophagic degradation of aggregated huntingtin.
  - term:
      id: GO:0032418
      label: lysosome localization
    evidence_type: IMP
    original_reference_id: PMID:16192271
    review:
      summary: HDAC6 affects lysosome localization during autophagy.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of autophagy regulation.
      supported_by:
        - reference_id: PMID:16192271
          supporting_text: 2005 Sep 28. HDAC6 and microtubules are required for 
            autophagic degradation of aggregated huntingtin.
  - term:
      id: GO:0070301
      label: cellular response to hydrogen peroxide
    evidence_type: IMP
    original_reference_id: PMID:18606987
    review:
      summary: HDAC6 affects cellular response to H2O2 through peroxiredoxin 
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of peroxiredoxin deacetylation.
      supported_by:
        - reference_id: PMID:18606987
          supporting_text: HDAC6 is a specific deacetylase of peroxiredoxins and
            is involved in redox regulation.
  - term:
      id: GO:0005875
      label: microtubule associated complex
    evidence_type: IDA
    original_reference_id: PMID:19228685
    review:
      summary: HDAC6 associates with microtubule complexes.
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0005901
      label: caveola
    evidence_type: IDA
    original_reference_id: PMID:18356165
    review:
      summary: HDAC6 localizes to caveolae in EGFR signaling context.
      action: KEEP_AS_NON_CORE
      reason: Context-specific localization in EGFR signaling.
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IPI
    original_reference_id: PMID:18356165
    review:
      summary: HDAC6 binds beta-catenin.
      action: KEEP_AS_NON_CORE
      reason: Signaling pathway interaction.
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0008017
      label: microtubule binding
    evidence_type: IDA
    original_reference_id: PMID:19228685
    review:
      summary: Direct demonstration of HDAC6 microtubule binding.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0010634
      label: positive regulation of epithelial cell migration
    evidence_type: IMP
    original_reference_id: PMID:12024216
    review:
      summary: HDAC6 promotes cell motility through tubulin deacetylation.
      action: ACCEPT
      reason: Core function - HDAC6 regulates cell motility through effects on 
        microtubule dynamics [PMID:12024216].
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: overexpression of HDAC6 promotes chemotactic cell 
            movement, supporting the idea that HDAC6-mediated deacetylation 
            regulates microtubule-dependent cell motility
  - term:
      id: GO:0031252
      label: cell leading edge
    evidence_type: IDA
    original_reference_id: PMID:12024216
    review:
      summary: HDAC6 localizes to cell leading edge.
      action: ACCEPT
      reason: Relevant to cell motility function [PMID:12024216].
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: Acetylated alpha-tubulin is most abundant in stable 
            microtubules but is absent from dynamic cellular structures such as 
            neuronal growth cones and the leading edges of fibroblasts
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:19228685
    review:
      summary: Direct demonstration of tubulin deacetylase activity.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0043014
      label: alpha-tubulin binding
    evidence_type: IDA
    original_reference_id: PMID:19228685
    review:
      summary: HDAC6 binds alpha-tubulin, its primary substrate.
      action: ACCEPT
      reason: Core molecular function - alpha-tubulin is the primary substrate.
      supported_by:
        - reference_id: PMID:19228685
          supporting_text: 2009 Feb 18. The protein farnesyltransferase 
            regulates HDAC6 activity in a microtubule-dependent manner.
  - term:
      id: GO:0043242
      label: negative regulation of protein-containing complex disassembly
    evidence_type: IMP
    original_reference_id: PMID:15916966
    review:
      summary: HDAC6 affects HSP90 complex stability through deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of HSP90 deacetylation.
      supported_by:
        - reference_id: PMID:15916966
          supporting_text: HDAC6 regulates Hsp90 acetylation and 
            chaperone-dependent activation of glucocorticoid receptor.
  - term:
      id: GO:0045861
      label: negative regulation of proteolysis
    evidence_type: IMP
    original_reference_id: PMID:18356165
    review:
      summary: HDAC6 affects proteolysis in EGFR signaling context.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect.
      supported_by:
        - reference_id: PMID:18356165
          supporting_text: 2008 Mar 20. HDAC6 is required for epidermal growth 
            factor-induced beta-catenin nuclear localization.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12024216
    review:
      summary: HDAC6 localizes to perinuclear region (MTOC/aggresome region).
      action: ACCEPT
      reason: Relevant to aggresome function - aggresomes form at the MTOC in 
        the perinuclear region.
      supported_by:
        - reference_id: PMID:12024216
          supporting_text: HDAC6 is a microtubule-associated deacetylase.
  - term:
      id: GO:0051879
      label: Hsp90 protein binding
    evidence_type: IDA
    original_reference_id: PMID:15916966
    review:
      summary: HDAC6 binds and deacetylates HSP90.
      action: ACCEPT
      reason: Core molecular function - HSP90 is a major HDAC6 substrate 
        [PMID:15916966].
      supported_by:
        - reference_id: PMID:15916966
          supporting_text: HDAC6 functions as an Hsp90 deacetylase
  - term:
      id: GO:0005874
      label: microtubule
    evidence_type: IDA
    original_reference_id: PMID:12620231
    review:
      summary: HDAC6 associates with microtubules (study on SIRT2-HDAC6 
        interaction).
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:12620231
          supporting_text: SIRT2 colocalizes and interacts in vivo with HDAC6, 
            another tubulin deacetylase
  - term:
      id: GO:0042903
      label: tubulin deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:12620231
    review:
      summary: HDAC6 tubulin deacetylase activity (study on SIRT2-HDAC6 
        interaction).
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:12620231
          supporting_text: HDAC6, another tubulin deacetylase
  - term:
      id: GO:0042826
      label: histone deacetylase binding
    evidence_type: IPI
    original_reference_id: PMID:12620231
    review:
      summary: HDAC6 interacts with SIRT2.
      action: KEEP_AS_NON_CORE
      reason: Interaction with another tubulin deacetylase (SIRT2) - regulatory 
        relationship.
      supported_by:
        - reference_id: PMID:12620231
          supporting_text: SIRT2 colocalizes and interacts in vivo with HDAC6
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: ISS
    original_reference_id: PMID:11861901
    review:
      summary: Cytoplasmic localization by sequence similarity.
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:11861901
          supporting_text: Identification of HDAC10, a novel class II human 
            histone deacetylase containing a leucine-rich domain.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: ISS
    original_reference_id: PMID:11861901
    review:
      summary: HDAC6 binds other enzymes.
      action: KEEP_AS_NON_CORE
      reason: Generic binding term.
      supported_by:
        - reference_id: PMID:11861901
          supporting_text: Identification of HDAC10, a novel class II human 
            histone deacetylase containing a leucine-rich domain.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: ISS
    original_reference_id: PMID:11861901
    review:
      summary: HDAC6 may affect transcription through deacetylase activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: HDAC6 is predominantly cytoplasmic and deacetylates non-histone 
        substrates. Its role in transcriptional regulation is indirect and not a
        core function.
      supported_by:
        - reference_id: PMID:11861901
          supporting_text: Identification of HDAC10, a novel class II human 
            histone deacetylase containing a leucine-rich domain.
  - term:
      id: GO:0000118
      label: histone deacetylase complex
    evidence_type: IDA
    original_reference_id: PMID:11948178
    review:
      summary: HDAC6 interacts with HDAC11.
      action: KEEP_AS_NON_CORE
      reason: While HDAC6 can interact with other HDACs, it does not primarily 
        function as part of nuclear HDAC complexes.
      supported_by:
        - reference_id: PMID:11948178
          supporting_text: 2002 Apr 10. Cloning and functional characterization 
            of HDAC11, a novel member of the human histone deacetylase family.
references:
  - 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, accompanied by conservative changes to GO 
      terms applied by UniProt
    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, based on on
      inter-ontology links
    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:10220385
    title: Three proteins define a class of human histone deacetylases related 
      to yeast Hda1p.
    findings:
      - statement: Original identification of HDAC6 as a histone deacetylase 
          family member
  - id: PMID:11861901
    title: Identification of HDAC10, a novel class II human histone deacetylase 
      containing a leucine-rich domain.
    findings: []
  - id: PMID:11948178
    title: Cloning and functional characterization of HDAC11, a novel member of 
      the human histone deacetylase family.
    findings:
      - statement: HDAC6 interacts with HDAC11
  - id: PMID:12024216
    title: HDAC6 is a microtubule-associated deacetylase.
    findings:
      - statement: HDAC6 is the tubulin deacetylase
      - statement: HDAC6 is cytoplasmic and associates with microtubules
      - statement: HDAC6 promotes cell motility through tubulin deacetylation
  - id: PMID:12354939
    title: Histone deacetylase 6 binds polyubiquitin through its zinc finger 
      (PAZ domain) and copurifies with deubiquitinating enzymes.
    findings:
      - statement: HDAC6 ZnF-UBP domain binds polyubiquitin
  - id: PMID:12535528
    title: Ligand-dependent nuclear receptor corepressor LCoR functions by 
      histone deacetylase-dependent and -independent mechanisms.
    findings: []
  - id: PMID:12620231
    title: The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin 
      deacetylase.
    findings:
      - statement: HDAC6 interacts with SIRT2, another tubulin deacetylase
  - id: PMID:14675537
    title: The deacetylase HDAC6 regulates aggresome formation and cell 
      viability in response to misfolded protein stress.
    findings:
      - statement: HDAC6 binds polyubiquitinated misfolded proteins and dynein 
          motors
      - statement: HDAC6 is essential for aggresome formation
      - statement: HDAC6 is crucial for managing misfolded protein stress
  - id: PMID:15916966
    title: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation 
      of glucocorticoid receptor.
    findings:
      - statement: HDAC6 deacetylates HSP90 to regulate its chaperone activity
  - id: PMID:16192271
    title: HDAC6 and microtubules are required for autophagic degradation of 
      aggregated huntingtin.
    findings:
      - statement: HDAC6-dependent retrograde transport required for autophagy
  - id: PMID:16919237
    title: Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the 
      Hsp90 chaperone.
    findings: []
  - id: PMID:17604723
    title: HEF1-dependent Aurora A activation induces disassembly of the primary
      cilium.
    findings:
      - statement: HDAC6 phosphorylation by Aurora A promotes cilium disassembly
      - statement: HDAC6 localizes to ciliary basal body
  - id: PMID:17785525
    title: HDAC6 controls major cell response pathways to cytotoxic accumulation
      of protein aggregates.
    findings: []
  - id: PMID:17872950
    title: Critical and functional regulation of CHOP (C/EBP homologous protein)
      through the N-terminal portion.
    findings: []
  - id: PMID:18316616
    title: Selective inhibition of histone deacetylase 2 silences progesterone 
      receptor-mediated signaling.
    findings: []
  - id: PMID:18356165
    title: HDAC6 is required for epidermal growth factor-induced beta-catenin 
      nuclear localization.
    findings: []
  - id: PMID:18606987
    title: HDAC6 is a specific deacetylase of peroxiredoxins and is involved in 
      redox regulation.
    findings:
      - statement: HDAC6 deacetylates peroxiredoxins, affecting their H2O2 
          reducing activity
  - id: PMID:18636984
    title: Histone deacetylase 6 interacts with the microtubule-associated 
      protein tau.
    findings: []
  - id: PMID:18852123
    title: Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 
      chaperone function.
    findings: []
  - id: PMID:19033385
    title: FAT10 interacts with HDAC6 and localizes to aggresomes
    findings: []
  - id: PMID:19036992
    title: Direct binding with histone deacetylase 6 mediates the reversible 
      recruitment of parkin to the centrosome.
    findings: []
  - id: PMID:19081074
    title: A BBSome subunit links ciliogenesis, microtubule stability, and 
      acetylation.
    findings: []
  - id: PMID:19167333
    title: A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in 
      postmitotic neurons.
    findings: []
  - id: PMID:19228685
    title: The protein farnesyltransferase regulates HDAC6 activity in a 
      microtubule-dependent manner.
    findings: []
  - id: PMID:19457097
    title: Tau--an inhibitor of deacetylase HDAC6 function.
    findings:
      - statement: Tau binds HDAC6 and inhibits its tubulin deacetylase activity
  - id: PMID:19893491
    title: CYLD negatively regulates cell-cycle progression by inactivating 
      HDAC6 and increasing the levels of acetylated tubulin.
    findings: []
  - id: PMID:20029029
    title: Regulation of epidermal growth factor receptor trafficking by lysine 
      deacetylase HDAC6.
    findings: []
  - id: PMID:20308065
    title: TPPP/p25 promotes tubulin acetylation by inhibiting histone 
      deacetylase 6.
    findings: []
  - id: PMID:20457763
    title: Disease-causing mutations in parkin impair mitochondrial 
      ubiquitination, aggregation, and HDAC6-dependent mitophagy.
    findings: []
  - id: PMID:21220424
    title: Regulation of Tat acetylation and transactivation activity by the 
      microtubule-associated deacetylase HDAC6.
    findings: []
  - id: PMID:21532619
    title: The HTLV-1 Tax protein inhibits formation of stress granules by 
      interacting with histone deacetylase 6.
    findings: []
  - id: PMID:21753002
    title: Parkin interacts with Ambra1 to induce mitophagy.
    findings: []
  - id: PMID:21847094
    title: Class IIb HDAC6 regulates endothelial cell migration and angiogenesis
      by deacetylation of cortactin.
    findings: []
  - id: PMID:21952047
    title: PKC alpha regulates Sendai virus-mediated interferon induction 
      through HDAC6 and β-catenin.
    findings: []
  - id: PMID:22193721
    title: A novel GRK2/HDAC6 interaction modulates cell spreading and motility.
    findings: []
  - id: PMID:22645275
    title: Identification of novel ATP13A2 interactors and their role in 
      α-synuclein misfolding and toxicity.
    findings: []
  - id: PMID:23084749
    title: Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress
      cancer cell differentiation.
    findings: []
  - id: PMID:23093407
    title: Rho-associated coiled-coil kinase (ROCK) protein controls microtubule
      dynamics in a novel signaling pathway that regulates cell migration.
    findings: []
  - id: PMID:23322205
    title: A novel small molecule hydroxamate preferentially inhibits HDAC6 
      activity and tumour growth.
    findings: []
  - id: PMID:23580651
    title: HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and 
      tubulin acetylation.
    findings: []
  - id: PMID:23962722
    title: Acetylation of the KXGS motifs in tau is a critical determinant in 
      modulation of tau aggregation and clearance.
    findings: []
  - id: PMID:24413532
    title: Differential regulation of estrogen receptor α expression in breast 
      cancer cells by metastasis-associated protein 1.
    findings: []
  - id: PMID:24658140
    title: The mammalian-membrane two-hybrid assay (MaMTH) for probing 
      membrane-protein interactions in human cells.
    findings: []
  - id: PMID:24687993
    title: Fam65b is important for formation of the HDAC6-dysferlin protein 
      complex during myogenic cell differentiation.
    findings: []
  - id: PMID:25422469
    title: Disruption of FAT10-MAD2 binding inhibits tumor progression.
    findings: []
  - id: PMID:25548531
    title: 'ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.'
    findings: []
  - id: PMID:26246421
    title: Deacetylation of α-tubulin and cortactin is required for HDAC6 to 
      trigger ciliary disassembly.
    findings:
      - statement: HDAC6 deacetylates both alpha-tubulin and cortactin for 
          cilium disassembly
  - id: PMID:27556504
    title: FAM65B controls the proliferation of transformed and primary T cells.
    findings: []
  - id: PMID:28105056
    title: HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement 
      in Motor Neurons Derived from the Induced Pluripotent Stem Cells of 
      Peripheral Neuropathy Patients with HSPB1 Mutation.
    findings: []
  - id: PMID:28386764
    title: Roles of tau protein in health and disease.
    findings: []
  - id: PMID:28516954
    title: Histone deacetylase 10 structure and molecular function as a 
      polyamine deacetylase.
    findings:
      - statement: Note - this paper is about HDAC10, not HDAC6
  - id: PMID:29281743
    title: HDAC6 controls innate immune and autophagy responses to TLR-mediated 
      signalling by the intracellular bacteria Listeria monocytogenes.
    findings: []
  - id: PMID:31857589
    title: Requirement for p62 acetylation in the aggregation of ubiquitylated 
      proteins under nutrient stress.
    findings:
      - statement: HDAC6 deacetylates p62/SQSTM1
  - id: PMID:31980649
    title: Extensive rewiring of the EGFR network in colorectal cancer cells 
      expressing transforming levels of KRAS(G13D).
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: Reactome:R-HSA-3371511
    title: HSF1 activation
    findings: []
  - id: Reactome:R-HSA-5324632
    title: Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing 
      protein aggregates
    findings: []
  - id: Reactome:R-HSA-5618331
    title: HDAC6 deacetylates microtubules
    findings: []
  - id: Reactome:R-HSA-5620920
    title: Cargo trafficking to the periciliary membrane
    findings: []
  - id: Reactome:R-HSA-9646348
    title: PolyUb-Misfolded Proteins:HDAC6 bind dynein motor
    findings: []
  - id: Reactome:R-HSA-9646679
    title: PolyUb-Misfolded proteins bind vimentin to form aggresome
    findings: []
  - id: Reactome:R-HSA-9646685
    title: Aggresome dissociates from dynein and microtubule
    findings: []
  - id: file:human/HDAC6/HDAC6-deep-research-falcon.md
    title: Deep research report on HDAC6
    findings: []
core_functions:
  - description: HDAC6 deacetylates alpha-tubulin at K40, regulating microtubule
      stability and dynamics. This is one of the best-characterized functions of
      HDAC6.
    molecular_function:
      id: GO:0042903
      label: tubulin deacetylase activity
  - description: HDAC6 is a Zn2+-dependent deacetylase that removes acetyl 
      groups from lysine residues of various non-histone substrates including 
      tubulin, HSP90, cortactin, peroxiredoxins, and other cytoplasmic proteins.
    molecular_function:
      id: GO:0033558
      label: protein lysine deacetylase activity
  - description: HDAC6 binds and deacetylates HSP90, regulating its chaperone 
      activity. This affects client protein maturation including steroid hormone
      receptors.
    molecular_function:
      id: GO:0051879
      label: Hsp90 protein binding
  - description: HDAC6 binds ubiquitin via its C-terminal ZnF-UBP domain. This 
      is essential for recognizing polyubiquitinated misfolded proteins and 
      transporting them to aggresomes.
    molecular_function:
      id: GO:0043130
      label: ubiquitin binding
  - description: HDAC6 is essential for aggresome formation. It binds 
      polyubiquitinated misfolded proteins via its ZnF-UBP domain and recruits 
      dynein motors for retrograde transport to the MTOC.
    molecular_function:
      id: GO:0070840
      label: dynein complex binding
    directly_involved_in:
      - id: GO:0070842
        label: aggresome assembly
  - description: HDAC6 promotes cilium disassembly through deacetylation of 
      alpha-tubulin and cortactin at the ciliary basal body. This is regulated 
      by Aurora A phosphorylation.
    molecular_function:
      id: GO:0042903
      label: tubulin deacetylase activity
    directly_involved_in:
      - id: GO:0061523
        label: cilium disassembly

HDAC6

Gene Description

Existing Annotations Review

Core Functions

HDAC6 deacetylates alpha-tubulin at K40, regulating microtubule stability and dynamics. This is one of the best-characterized functions of HDAC6.

HDAC6 is a Zn2+-dependent deacetylase that removes acetyl groups from lysine residues of various non-histone substrates including tubulin, HSP90, cortactin, peroxiredoxins, and other cytoplasmic proteins.

HDAC6 binds and deacetylates HSP90, regulating its chaperone activity. This affects client protein maturation including steroid hormone receptors.

HDAC6 binds ubiquitin via its C-terminal ZnF-UBP domain. This is essential for recognizing polyubiquitinated misfolded proteins and transporting them to aggresomes.

HDAC6 is essential for aggresome formation. It binds polyubiquitinated misfolded proteins via its ZnF-UBP domain and recruits dynein motors for retrograde transport to the MTOC.

HDAC6 promotes cilium disassembly through deacetylation of alpha-tubulin and cortactin at the ciliary basal body. This is regulated by Aurora A phosphorylation.

References

📚 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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