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.
| 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 Ξ²-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 Ξ±-synuclein misfolding and toxicity. |
| GO:0005515 protein binding | IPI PMID:23084749 Regulation of CD133 by HDAC6 promotes Ξ²-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 Ξ²-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 Ξ±-tubulin and cortactin is required for HDA... | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization. Reason: Core localization. Supporting Evidence: PMID:26246421 Deacetylation of Ξ±-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly. |
| GO:0005813 centrosome | IDA PMID:26246421 Deacetylation of Ξ±-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 Ξ±-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly. |
| GO:0036064 ciliary basal body | IDA PMID:26246421 Deacetylation of Ξ±-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 Ξ±-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly. |
| GO:0061523 cilium disassembly | IDA PMID:26246421 Deacetylation of Ξ±-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 Ξ±-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 Ξ± 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 Ξ± 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 Ξ± 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 Ξ± 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 The ubiquitin-like modifier FAT10 interacts with HDAC6 and l... | 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. |
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