HDAC5 is a class IIa histone deacetylase that acts mainly as a signal-regulated transcriptional corepressor. Its N-terminal extension binds MEF2 and other DNA-binding transcription factors (HIF-1alpha, GCM1, GATA3, XBP1s, RFXANK) and recruits the catalytically active HDAC3/N-CoR/SMRT complex and HP1, repressing target genes such as MEF2-dependent muscle genes, GLUT4, FGF2/SLIT2 in endothelium and syncytin-1 in trophoblasts. Its C-terminal deacetylase domain carries a His in place of the catalytic Tyr and has only weak intrinsic activity on acetyl-lysine. Phosphorylation of Ser259 and Ser498 by CaMK, AMPK, PKD, SIK1 and related kinases creates 14-3-3 binding sites that drive CRM1-dependent nuclear export, derepressing targets; this couples calcium, energy and other signals to gene expression in muscle differentiation, cardiac hypertrophy, angiogenesis, placental cell fusion and neuronal adaptation. In some contexts it can enhance transcription, as for HIF-1alpha.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000118 histone deacetylase complex | IBA GO_REF:0000033 | ACCEPT | Summary: HDAC5 associates with HDAC3 and the SMRT/N-CoR corepressor machinery, i.e. a histone deacetylase complex. Reason: HDAC5 co-purifies with HDAC3 (PMID:10220385, PMID:10869435) and class II HDACs bridge transcription factors to the SMRT/N-CoR-HDAC3 complex (PMID:11804585). Membership of an HDAC-containing corepressor complex is central to its mechanism. Supporting Evidence: PMID:10220385 HDAC5 associates only with HDAC3, though it is possible that the expression levels were too low to detect other associated factors. PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity. |
| GO:0000118 histone deacetylase complex | TAS PMID:12711221 Class II histone deacetylases: versatile regulators. | ACCEPT | Summary: HDAC5 associates with HDAC3 and the SMRT/N-CoR corepressor machinery, i.e. a histone deacetylase complex. Reason: HDAC5 co-purifies with HDAC3 (PMID:10220385, PMID:10869435) and class II HDACs bridge transcription factors to the SMRT/N-CoR-HDAC3 complex (PMID:11804585). Membership of an HDAC-containing corepressor complex is central to its mechanism. Supporting Evidence: PMID:10220385 HDAC5 associates only with HDAC3, though it is possible that the expression levels were too low to detect other associated factors. PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity. PMID:12711221 Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:16236793 Class II histone deacetylases confer signal responsiveness t... | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:16236793 HDAC4 and HDAC5 interact with the ankyrin repeats of ANKRA2 and RFXANK and, through association with RFXANK, repress MHC II promoter activation. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000002 | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. file:human/HDAC5/HDAC5-uniprot.txt Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:10983972 Regulation of skeletal myogenesis by association of the MEF2... | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:19351956 HDAC5 is a repressor of angiogenesis and determines the angi... | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:19351956 In summary, HDAC5 represses angiogenic genes, such as FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t... | ACCEPT | Summary: HDAC5 represses RNA polymerase II-dependent transcription as a signal-regulated corepressor of MEF2 and other DNA-binding factors. Reason: Repression of Pol II target genes (MEF2 targets, MHC II, FGF2/SLIT2, GCM1 targets) is the best-supported biological role of HDAC5 and is core. Supporting Evidence: PMID:23867755 The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:19351956 HDAC5 is a repressor of angiogenesis and determines the angi... | MODIFY | Summary: ChIP shows HDAC5 at the FGF2 and SLIT2 promoters, which it represses (contributes_to transcription cis-regulatory region binding). Reason: GO:0000976 is_a GO:0043565 sequence-specific DNA binding, so even with contributes_to it describes DNA binding by a complex that is not defined in the paper. HDAC5 has no DNA-binding domain; ChIP occupancy reflects recruitment. What the paper shows is promoter-associated repression independent of MEF2 binding, i.e. transcription corepressor activity. This differs from the HDAC4 review, which proposed GO:0000976 as a replacement; the parentage of GO:0000976 argues against that choice. Proposed replacements: transcription corepressor activity Supporting Evidence: PMID:19351956 Chromatin immunoprecipitation assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. PMID:19351956 In summary, HDAC5 represses angiogenic genes, such as FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. PMID:19351956 The antiangiogenic activity of HDAC5 was independent of myocyte enhancer factor-2 binding and its deacetylase activity but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | MODIFY | Summary: Flagged by FRR:0009: sequence-specific DNA binding asserted for a protein with no DNA-binding domain; HDAC5 is recruited to the ESR1 locus within MTA1 complexes. Reason: PMID:24413532 (abstract-only in cache) reports that class II HDACs take part in MTA1-mediated regulation of ESR1, where the DNA-binding factors are TFAP2C and IFI16. Nothing indicates direct sequence-specific DNA binding by HDAC5, which lacks any DNA-binding domain. The experiment is not in question; the activity class is. Because the effect on ESR1 differs between cell lines, the neutral parent GO:0003712 transcription coregulator activity is proposed rather than corepressor. Proposed replacements: transcription coregulator activity Supporting Evidence: PMID:24413532 Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERΞ±. file:human/HDAC5/HDAC5-uniprot.txt Belongs to the histone deacetylase family. HD type 2 subfamily. |
| GO:0001216 DNA-binding transcription activator activity | IMP PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph... | MODIFY | Summary: Flagged by FRR:0009. PMID:19071119 shows HDAC5 enhances HIF-1alpha transactivation by binding its inhibitory domain, displacing FIH-1 and favouring p300 recruitment. Reason: The IMP evidence is sound but describes coactivation of a DNA-binding factor, not DNA-binding activator activity: HDAC5 has no DNA-binding domain and the paper does not test DNA binding. GO:0003700-branch usage excludes chromatin enzymes without a DNA-binding domain. Replaced with transcription coactivator activity, consistent with the HDAC4 review of the same paper. This is a context-specific, non-core activity of HDAC5 (its main role is corepression). Proposed replacements: transcription coactivator activity Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 enhanced transactivation by HIF-1alpha without stabilizing HIF-1alpha. PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). PMID:19071119 These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300. |
| GO:0001222 transcription corepressor binding | IPI PMID:10898795 BCoR, a novel corepressor involved in BCL-6 repression. | ACCEPT | Summary: HDAC5 co-immunoprecipitates with the BCL6 corepressor BCoR. Reason: Binding of corepressors (BCoR here; N-CoR/SMRT elsewhere) is how HDAC5 joins repressor complexes; the term is informative and supported. Supporting Evidence: PMID:10898795 Additionally, both forms of BCoR can associate with specific HDACs of both class I and class II HDACs, which suggests that histone/protein deacetylation is a mechanism for BCoR-mediated repression. |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Chromatin binding transferred from the rat ortholog. Reason: HDAC5 occupies promoters (ChIP at FGF2/SLIT2) and associates with HP1, but through recruitment by DNA-binding partners rather than by an intrinsic chromatin-binding domain. Acceptable as a non-core description. Supporting Evidence: PMID:19351956 Chromatin immunoprecipitation assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. PMID:12242305 Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. |
| GO:0004407 histone deacetylase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Histone deacetylase activity of HDAC5 (IBA). Reason: Class IIa HDACs, including HDAC5, carry His in place of the catalytic Tyr conserved in other HDACs and are about 1000-fold less active than class I enzymes on acetyl-lysine substrates (PMID:17956988). Deacetylase activity measured in HDAC5 immunoprecipitates (PMID:10220385, PMID:10869435) co-purifies with HDAC3, and reconstitution shows that class II HDACs do not contribute to the activity of the SMRT/N-CoR-HDAC3 complex (PMID:11804585). The in vitro histone deacetylase activity is real but weak and of uncertain physiological relevance; HDAC5 represses chromatin mainly by recruiting HDAC3 complexes. Following the promiscuous-activity tiers, this is marked as an over-annotation rather than removed. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN008143312 SUPPORTS SOURCE BUT NOT TARGET Deep ancestral node spanning class I and class II HDACs; activity is well grounded for class I members, but vertebrate class IIa descendants replaced the catalytic Tyr with His and retain only weak activity. UniProtKB:Q9UQL6 SOURCE WEAK OR INFERRED HDAC5 own IDA rows (PMID:10220385, PMID:10869435) measure immunoprecipitate activity that co-purifies with HDAC3; expected and not circular, but weak as evidence of intrinsic activity. Supporting Evidence: PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. PMID:17956988 A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. |
| GO:0004407 histone deacetylase activity | IDA PMID:10220385 Three proteins define a class of human histone deacetylases ... | MARK AS OVER ANNOTATED | Summary: Histone deacetylase activity of HDAC5 (IDA). Reason: Class IIa HDACs, including HDAC5, carry His in place of the catalytic Tyr conserved in other HDACs and are about 1000-fold less active than class I enzymes on acetyl-lysine substrates (PMID:17956988). Deacetylase activity measured in HDAC5 immunoprecipitates (PMID:10220385, PMID:10869435) co-purifies with HDAC3, and reconstitution shows that class II HDACs do not contribute to the activity of the SMRT/N-CoR-HDAC3 complex (PMID:11804585). The in vitro histone deacetylase activity is real but weak and of uncertain physiological relevance; HDAC5 represses chromatin mainly by recruiting HDAC3 complexes. Following the promiscuous-activity tiers, this is marked as an over-annotation rather than removed. Supporting Evidence: PMID:10220385 HDAC1 and HDAC6 possess comparable activity, whereas that of HDAC4 and HDAC5 is somewhat reduced. PMID:10220385 HDAC5 associates only with HDAC3, though it is possible that the expression levels were too low to detect other associated factors. PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. PMID:17956988 A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. |
| GO:0004407 histone deacetylase activity | IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | MARK AS OVER ANNOTATED | Summary: Histone deacetylase activity of HDAC5 (IDA). Reason: Class IIa HDACs, including HDAC5, carry His in place of the catalytic Tyr conserved in other HDACs and are about 1000-fold less active than class I enzymes on acetyl-lysine substrates (PMID:17956988). Deacetylase activity measured in HDAC5 immunoprecipitates (PMID:10220385, PMID:10869435) co-purifies with HDAC3, and reconstitution shows that class II HDACs do not contribute to the activity of the SMRT/N-CoR-HDAC3 complex (PMID:11804585). The in vitro histone deacetylase activity is real but weak and of uncertain physiological relevance; HDAC5 represses chromatin mainly by recruiting HDAC3 complexes. Following the promiscuous-activity tiers, this is marked as an over-annotation rather than removed. Supporting Evidence: PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. PMID:17956988 A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. |
| GO:0004407 histone deacetylase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Histone deacetylase activity of HDAC5 (IEA). Reason: Class IIa HDACs, including HDAC5, carry His in place of the catalytic Tyr conserved in other HDACs and are about 1000-fold less active than class I enzymes on acetyl-lysine substrates (PMID:17956988). Deacetylase activity measured in HDAC5 immunoprecipitates (PMID:10220385, PMID:10869435) co-purifies with HDAC3, and reconstitution shows that class II HDACs do not contribute to the activity of the SMRT/N-CoR-HDAC3 complex (PMID:11804585). The in vitro histone deacetylase activity is real but weak and of uncertain physiological relevance; HDAC5 represses chromatin mainly by recruiting HDAC3 complexes. Following the promiscuous-activity tiers, this is marked as an over-annotation rather than removed. Supporting Evidence: PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. PMID:17956988 A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. |
| GO:0005080 protein kinase C binding | IPI PMID:20188095 Protein kinase C-related kinase targets nuclear localization... | KEEP AS NON CORE | Summary: PKN2 (PRK2) was purified as an HDAC5-interacting kinase that phosphorylates Thr292 in the NLS. Reason: HDAC5 is a substrate of PKN1/PKN2; the binding reflects regulation of HDAC5 nuclear import rather than a function of HDAC5. Supporting Evidence: PMID:20188095 Using a biochemical purification strategy, we identified protein kinase C-related kinase-2 (PRK2) as an HDAC5-interacting protein. |
| GO:0005515 protein binding | IPI PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | MODIFY | Summary: HDAC5 interacts with HDAC3 when released from 14-3-3. Reason: The informative function is histone deacetylase binding (HDAC3), already annotated from PMID:23867755. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression. |
| GO:0005515 protein binding | IPI PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | MODIFY | Summary: Phosphorylation-dependent binding of 14-3-3 proteins, which sequesters HDAC5 in the cytoplasm. Reason: The informative function is 14-3-3 protein binding, the key regulatory interaction controlling HDAC5 localization. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm. |
| GO:0005515 protein binding | IPI PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | MODIFY | Summary: Phosphorylation-dependent binding of 14-3-3 proteins, which sequesters HDAC5 in the cytoplasm. Reason: The informative function is 14-3-3 protein binding, the key regulatory interaction controlling HDAC5 localization. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm. |
| GO:0005515 protein binding | IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1... | REMOVE | Summary: Generic protein binding with 14-3-3 zeta (proteomic 14-3-3 affinity screen). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:15194749 Functional interaction between class II histone deacetylases... | REMOVE | Summary: Generic protein binding with HSV-1 ICP0 (viral). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:15923258 An expression screen reveals modulators of class II histone ... | MODIFY | Summary: HDAC5 recruits 14-3-3 (SFN) when its N-terminal sites are phosphorylated. Reason: Replaced by 14-3-3 protein binding, which captures the regulatory interaction. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:15923258 Phosphorylation of a set of conserved serine residues in the N-terminal extensions of class II HDACs creates binding sites for 14-3-3 chaperone proteins, which trigger nuclear export of these HDACs, thereby derepressing specific target genes in a signal-dependent manner. |
| GO:0005515 protein binding | IPI PMID:16919237 Breast cancer metastasis suppressor 1 (BRMS1) is stabilized ... | REMOVE | Summary: Generic protein binding with BRMS1. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:17075044 Interaction of GATA-3/T-bet transcription factors regulates ... | MODIFY | Summary: GATA3 recruits HDAC3/HDAC5 in a phosphorylation-dependent manner to repress FUT7. Reason: The partner is a DNA-binding RNA polymerase II transcription factor and the paper shows HDAC5 acting as its corepressor. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:17075044 GATA-3 represses FUT7 transcription through phosphorylation-dependent interaction with HDAC-3 and HDAC-5, whereas T-bet promotes its transcription through recruiting CBP/P-300. |
| GO:0005515 protein binding | IPI PMID:17872950 Critical and functional regulation of CHOP (C/EBP homologous... | REMOVE | Summary: Generic protein binding with DDIT3/CHOP. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:18711143 Uncovering G protein-coupled receptor kinase-5 as a histone ... | REMOVE | Summary: Generic protein binding with mouse GRK5 (kinase-substrate). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph... | MODIFY | Summary: HDAC5 binds HIF-1alpha. Reason: The partner is a DNA-binding RNA polymerase II transcription factor; GO:0061629 is already annotated from the same paper. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). |
| GO:0005515 protein binding | IPI PMID:19666599 Human BAHD1 promotes heterochromatic gene silencing. | REMOVE | Summary: Generic protein binding with BAHD1. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... | REMOVE | Summary: Generic protein binding with MEF2C (high-throughput mammalian two-hybrid atlas). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:22649097 Sequence-specific recognition of a PxLPxI/L motif by an anky... | REMOVE | Summary: Generic protein binding with ANKRA2. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:23752268 The functional interactome landscape of the human histone de... | REMOVE | Summary: Generic protein binding with partners from an HDAC interactome AP-MS study. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:23752268 The functional interactome landscape of the human histone de... | REMOVE | Summary: Generic protein binding with partners from an HDAC interactome AP-MS study. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:23752268 The functional interactome landscape of the human histone de... | REMOVE | Summary: Generic protein binding with partners from an HDAC interactome AP-MS study. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:24229708 Runx3 inactivation is a crucial early event in the developme... | REMOVE | Summary: Generic protein binding with RUNX3. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | REMOVE | Summary: Generic protein binding with EP300. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:25752541 Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M... | REMOVE | Summary: Generic protein binding with ANKRA2. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Generic protein binding with 14-3-3 zeta (BioPlex). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding with LMO2 (HuRI). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Generic protein binding with 14-3-3 zeta (high-throughput). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:35044719 Proteome-scale mapping of binding sites in the unstructured ... | REMOVE | Summary: Generic protein binding with ANKRA2 (peptide screen). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Generic protein binding with 14-3-3 zeta (OpenCell). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the reported interaction. Functionally informative partner classes are captured by other terms in this review (14-3-3 protein binding, histone deacetylase binding, DNA-binding transcription factor binding). |
| GO:0005634 nucleus | IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | ACCEPT | Summary: HDAC5 is nuclear in its repressive, unphosphorylated state. Reason: Nuclear localization is required for its repressor activity (PMID:19351956) and is documented by several studies. Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression. |
| GO:0005634 nucleus | IDA PMID:11081517 Signal-dependent nuclear export of a histone deacetylase reg... | ACCEPT | Summary: HDAC5 is nuclear in its repressive, unphosphorylated state. Reason: Nuclear localization is required for its repressor activity (PMID:19351956) and is documented by several studies. Supporting Evidence: PMID:11081517 In proliferating undifferentiated myoblasts, HDAC5 was predominantly nuclear |
| GO:0005634 nucleus | IDA PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t... | ACCEPT | Summary: HDAC5 is nuclear in its repressive, unphosphorylated state. Reason: Nuclear localization is required for its repressor activity (PMID:19351956) and is documented by several studies. Supporting Evidence: PMID:23867755 We demonstrate that both GCM1 and HDAC5 are expressed in the syncytiotrophoblast layer of full-term placenta and the nuclei of BeWo cells. |
| GO:0005634 nucleus | IDA PMID:26157139 Filamin A is required in injured axons for HDAC5 activity an... | ACCEPT | Summary: HDAC5 is nuclear in its repressive, unphosphorylated state. Reason: Nuclear localization is required for its repressor activity (PMID:19351956) and is documented by several studies. Supporting Evidence: PMID:26157139 Under vehicle treatment conditions, GFP-HDAC5 was mostly nuclear, whereas, upon stimulation of the PKC pathway with I3A, GFP-HDAC5 relocalized to the cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: HDAC5 is nuclear in its repressive, unphosphorylated state. Reason: Nuclear localization is required for its repressor activity (PMID:19351956) and is documented by several studies. Supporting Evidence: file:human/HDAC5/HDAC5-uniprot.txt Shuttles between the nucleus and the cytoplasm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2220982 | ACCEPT | Summary: Reactome places HDAC5 in nucleoplasmic CSL/NCOR corepressor complexes. Reason: Consistent with the nuclear, chromatin-associated corepressor role. Supporting Evidence: Reactome:R-HSA-2220982 In the nucleus, NICD1 PEST domain mutants are expected to displace the NCOR co-repressor and form a complex with RBPJ and SNW1 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-350058 | ACCEPT | Summary: Reactome places HDAC5 in nucleoplasmic CSL/NCOR corepressor complexes. Reason: Consistent with the nuclear, chromatin-associated corepressor role. Supporting Evidence: Reactome:R-HSA-350058 DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: HDAC5 is exported to the cytoplasm after phosphorylation and 14-3-3 binding. Reason: Signal-dependent cytoplasmic relocalization is a defining property of HDAC5 regulation and is well documented. Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm. file:human/HDAC5/HDAC5-uniprot.txt Shuttles between the nucleus and the cytoplasm. |
| GO:0005737 cytoplasm | IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona... | ACCEPT | Summary: HDAC5 is exported to the cytoplasm after phosphorylation and 14-3-3 binding. Reason: Signal-dependent cytoplasmic relocalization is a defining property of HDAC5 regulation and is well documented. Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm. |
| GO:0005737 cytoplasm | IDA PMID:11081517 Signal-dependent nuclear export of a histone deacetylase reg... | ACCEPT | Summary: HDAC5 is exported to the cytoplasm after phosphorylation and 14-3-3 binding. Reason: Signal-dependent cytoplasmic relocalization is a defining property of HDAC5 regulation and is well documented. Supporting Evidence: PMID:11081517 Here we show that HDAC5 shuttles from the nucleus to the cytoplasm when myoblasts are triggered to differentiate. |
| GO:0005737 cytoplasm | IDA PMID:26157139 Filamin A is required in injured axons for HDAC5 activity an... | ACCEPT | Summary: HDAC5 is exported to the cytoplasm after phosphorylation and 14-3-3 binding. Reason: Signal-dependent cytoplasmic relocalization is a defining property of HDAC5 regulation and is well documented. Supporting Evidence: PMID:26157139 Under vehicle treatment conditions, GFP-HDAC5 was mostly nuclear, whereas, upon stimulation of the PKC pathway with I3A, GFP-HDAC5 relocalized to the cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: HDAC5 is exported to the cytoplasm after phosphorylation and 14-3-3 binding. Reason: Signal-dependent cytoplasmic relocalization is a defining property of HDAC5 regulation and is well documented. Supporting Evidence: file:human/HDAC5/HDAC5-uniprot.txt Shuttles between the nucleus and the cytoplasm. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosolic staining from the Human Protein Atlas. Reason: Consistent with the documented cytoplasmic pool of shuttling HDAC5. Supporting Evidence: PMID:11081517 Here we show that HDAC5 shuttles from the nucleus to the cytoplasm when myoblasts are triggered to differentiate. |
| GO:0006954 inflammatory response | TAS PMID:12711221 Class II histone deacetylases: versatile regulators. | KEEP AS NON CORE | Summary: Inflammatory response, via corepression of RARA and repression of miR-10a (UniProt, PMID:28167758). Reason: The cited review is abstract-only and does not mention inflammation, but UniProt records experimental evidence that HDAC5 with RARA represses miR-10a and influences the inflammatory response. Downstream, context-specific role. Supporting Evidence: file:human/HDAC5/HDAC5-uniprot.txt In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758). file:human/HDAC5/HDAC5-uniprot.txt Serves as a corepressor of RARA and causes its deacetylation (PubMed:28167758). |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to xenobiotic stimulus transferred from the rat ortholog by Ensembl Compara. Reason: Response and developmental terms from ortholog projection describe expression changes or downstream phenotypes, not an activity HDAC5 carries out in the process. No human or direct evidence supports HDAC5 executing this process. |
| GO:0010830 regulation of myotube differentiation | ISS GO_REF:0000024 | MODIFY | Summary: Regulation of myotube differentiation by similarity to mouse Hdac5. Reason: Correct but less specific than the evidence: HDAC5 negatively regulates myotube differentiation (GO:0010832, already annotated by IMP). Proposed replacements: negative regulation of myotube differentiation Supporting Evidence: PMID:11081517 An HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and acts as a dominant inhibitor of skeletal myogenesis, whereas a cytoplasmic HDAC5 mutant is unable to block efficiently the muscle differentiation program. |
| GO:0010832 negative regulation of myotube differentiation | IMP PMID:10983972 Regulation of skeletal myogenesis by association of the MEF2... | ACCEPT | Summary: HDAC5 represses MEF2-dependent myoblast differentiation; a non-exportable mutant blocks myogenesis. Reason: Directly shown in muscle cell models and the classic physiological context of HDAC5 corepressor function. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. |
| GO:0010832 negative regulation of myotube differentiation | IMP PMID:11081517 Signal-dependent nuclear export of a histone deacetylase reg... | ACCEPT | Summary: HDAC5 represses MEF2-dependent myoblast differentiation; a non-exportable mutant blocks myogenesis. Reason: Directly shown in muscle cell models and the classic physiological context of HDAC5 corepressor function. Supporting Evidence: PMID:11081517 An HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and acts as a dominant inhibitor of skeletal myogenesis, whereas a cytoplasmic HDAC5 mutant is unable to block efficiently the muscle differentiation program. |
| GO:0014823 response to activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to activity transferred from the rat ortholog by Ensembl Compara. Reason: Response and developmental terms from ortholog projection describe expression changes or downstream phenotypes, not an activity HDAC5 carries out in the process. No human or direct evidence supports HDAC5 executing this process. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Nuclear speck staining from the Human Protein Atlas. Reason: Single immunofluorescence observation without functional follow-up; plausible for a nuclear corepressor but not core. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: neuron differentiation transferred from the rat ortholog by Ensembl Compara. Reason: Response and developmental terms from ortholog projection describe expression changes or downstream phenotypes, not an activity HDAC5 carries out in the process. No human or direct evidence supports HDAC5 executing this process. |
| GO:0030183 B cell differentiation | TAS PMID:12711221 Class II histone deacetylases: versatile regulators. | UNDECIDED | Summary: B cell differentiation asserted by a review of class II HDACs (TAS). Reason: The review (abstract-only in cache) does not state a B-cell role for HDAC5, and no primary HDAC5 B-cell study was found. HDAC5 binds BCoR (PMID:10898795), but that is not evidence that HDAC5 acts in B cell activation or differentiation. |
| GO:0032869 cellular response to insulin stimulus | NAS PMID:18184930 AMP-activated protein kinase regulates GLUT4 transcription b... | MARK AS OVER ANNOTATED | Summary: Cellular response to insulin stimulus, based on a study of AMPK-mediated HDAC5 phosphorylation controlling GLUT4 transcription. Reason: PMID:18184930 studies AMPK/AICAR, not insulin stimulation. HDAC5 represses GLUT4 transcription (captured by GO:0000122); a role in the cellular response to insulin is an extrapolation. Supporting Evidence: PMID:18184930 Here, we report that AMP-activated protein kinase (AMPK) regulates GLUT4 transcription through the histone deacetylase (HDAC)5 transcriptional repressor. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: Generic protein-containing complex from rat ortholog projection. Reason: Too general; the specific complex is a histone deacetylase (HDAC3/N-CoR/SMRT) complex, already annotated. Proposed replacements: histone deacetylase complex Supporting Evidence: PMID:10220385 HDAC5 associates only with HDAC3, though it is possible that the expression levels were too low to detect other associated factors. |
| GO:0033558 protein lysine deacetylase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Protein lysine deacetylase activity toward non-histone substrates (GCM1 in placental cells; alpha-tubulin in injured axons). Reason: HDAC5 is required for deacetylation of GCM1 (PMID:23867755) and of tubulin in injured axons (PMID:26157139), but these studies show necessity, not that HDAC5 itself catalyses the reaction rather than recruited HDAC3; intrinsic class IIa activity on acetyl-lysine is very low (PMID:17956988). Kept as a non-core activity at the broad level that the evidence allows. Supporting Evidence: PMID:26157139 We have previously identified HDAC5 as an injury-regulated tubulin deacetylase that functions at the injury site to promote axon regeneration. PMID:23867755 The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. |
| GO:0033558 protein lysine deacetylase activity | IMP PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t... | KEEP AS NON CORE | Summary: Protein lysine deacetylase activity toward non-histone substrates (GCM1 in placental cells; alpha-tubulin in injured axons). Reason: HDAC5 is required for deacetylation of GCM1 (PMID:23867755) and of tubulin in injured axons (PMID:26157139), but these studies show necessity, not that HDAC5 itself catalyses the reaction rather than recruited HDAC3; intrinsic class IIa activity on acetyl-lysine is very low (PMID:17956988). Kept as a non-core activity at the broad level that the evidence allows. Supporting Evidence: PMID:23867755 The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. PMID:26157139 We have previously identified HDAC5 as an injury-regulated tubulin deacetylase that functions at the injury site to promote axon regeneration. PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. |
| GO:0040029 epigenetic regulation of gene expression | IBA GO_REF:0000033 | ACCEPT | Summary: Epigenetic regulation of gene expression (IBA). Reason: HDAC5 represses targets by recruiting HDAC3 complexes and HP1, changing histone acetylation/methylation at promoters; the phylogenetic inference is consistent with this. Supporting Evidence: PMID:12242305 Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity. |
| GO:0042113 B cell activation | TAS PMID:12711221 Class II histone deacetylases: versatile regulators. | UNDECIDED | Summary: B cell activation asserted by a review of class II HDACs (TAS). Reason: The review (abstract-only in cache) does not state a B-cell role for HDAC5, and no primary HDAC5 B-cell study was found. HDAC5 binds BCoR (PMID:10898795), but that is not evidence that HDAC5 acts in B cell activation or differentiation. |
| GO:0042220 response to cocaine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to cocaine transferred from the rat ortholog; mouse HDAC5 in the nucleus accumbens controls behavioral adaptation to chronic cocaine. Reason: Mouse loss-of-function data show HDAC5 limits transcriptional and behavioral responses to chronic cocaine (PMID:17988634). This is a tissue-specific consequence of its corepressor role, so non-core. Supporting Evidence: PMID:17988634 This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HDAC5 self-interaction in the HuRI binary screen. Reason: Class IIa HDACs oligomerize through their N-terminal glutamine-rich region (shown structurally for HDAC4); a high-throughput Y2H self-interaction is plausible but of unclear functional weight. |
| GO:0042826 histone deacetylase binding | IPI PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t... | ACCEPT | Summary: HDAC5 binds HDAC3. Reason: Recruitment of the catalytically active HDAC3 complex is how HDAC5 represses chromatin. Supporting Evidence: PMID:10220385 HDAC5 associates only with HDAC3, though it is possible that the expression levels were too low to detect other associated factors. PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression. |
| GO:0045814 negative regulation of gene expression, epigenetic | NAS PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | ACCEPT | Summary: Epigenetic repression of gene expression (MTA1-mediated regulation of ESR1). Reason: Consistent with HDAC5 acting in chromatin-modifying corepressor complexes. Supporting Evidence: PMID:24413532 Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERΞ±. PMID:12242305 Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. |
| GO:0045892 negative regulation of DNA-templated transcription | TAS PMID:12711221 Class II histone deacetylases: versatile regulators. | MODIFY | Summary: Negative regulation of DNA-templated transcription (TAS, review). Reason: True but less specific than the evidence: HDAC5 represses RNA polymerase II genes (GO:0000122, annotated with IDA/IMP). Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12711221 Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph... | KEEP AS NON CORE | Summary: HDAC5 enhances HIF-1alpha-dependent transcription. Reason: Supported by PMID:19071119 but context-specific and opposite to HDAC5's predominant corepressor role. Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 enhanced transactivation by HIF-1alpha without stabilizing HIF-1alpha. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph... | ACCEPT | Summary: HDAC5 binds a DNA-binding RNA polymerase II transcription factor (UniProtKB:Q61221). Reason: Binding sequence-specific transcription factors (MEF2, HIF-1alpha, GCM1, XBP1s, GATA3) is how HDAC5 is targeted to genes. Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:20408817 SUMO modification regulates the transcriptional activity of ... | ACCEPT | Summary: HDAC5 binds a DNA-binding RNA polymerase II transcription factor (UniProtKB:O35426-2). Reason: Binding sequence-specific transcription factors (MEF2, HIF-1alpha, GCM1, XBP1s, GATA3) is how HDAC5 is targeted to genes. Supporting Evidence: PMID:20408817 Indeed, out of all the HDACs (1 to 6), XBP1s strongly interacted with HDAC5 (Figure 5B). |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t... | ACCEPT | Summary: HDAC5 binds a DNA-binding RNA polymerase II transcription factor (UniProtKB:Q9NP62). Reason: Binding sequence-specific transcription factors (MEF2, HIF-1alpha, GCM1, XBP1s, GATA3) is how HDAC5 is targeted to genes. Supporting Evidence: PMID:23867755 The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: cellular response to lipopolysaccharide transferred from the rat ortholog by Ensembl Compara. Reason: Response and developmental terms from ortholog projection describe expression changes or downstream phenotypes, not an activity HDAC5 carries out in the process. No human or direct evidence supports HDAC5 executing this process. |
| GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis | IMP PMID:19351956 HDAC5 is a repressor of angiogenesis and determines the angi... | KEEP AS NON CORE | Summary: HDAC5 knockdown increases endothelial migration and sprouting; HDAC5 represses FGF2 and SLIT2. Reason: Well-supported tissue-specific consequence of HDAC5 corepressor activity in endothelial cells. Supporting Evidence: PMID:19351956 Silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting, and tube formation. PMID:19351956 In summary, HDAC5 represses angiogenic genes, such as FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. |
| GO:0140297 DNA-binding transcription factor binding | IEA GO_REF:0000117 | ACCEPT | Summary: DNA-binding transcription factor binding (ARBA). Reason: Supported experimentally by binding of MEF2, HIF-1alpha and GCM1. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). |
| GO:0140297 DNA-binding transcription factor binding | IPI PMID:12242305 Association of class II histone deacetylases with heterochro... | ACCEPT | Summary: IPI with mouse HP1alpha (CBX5). The claim (HDAC5 binds DNA-binding TFs) is true, but this evidence does not support it. Reason: Accepted as a claim because HDAC5 binds MEF2 and other DNA-binding factors (PMID:10983972, PMID:19071119). The supporting partner here, HP1alpha, is a chromodomain adaptor, not a DNA-binding transcription factor; recorded as a source defect. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. PMID:12242305 Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. |
| GO:0141221 histone deacetylase activity, hydrolytic mechanism | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Hydrolytic histone deacetylase activity mapped from EC 3.5.1.98 / RHEA:58196. Reason: Class IIa HDACs, including HDAC5, carry His in place of the catalytic Tyr conserved in other HDACs and are about 1000-fold less active than class I enzymes on acetyl-lysine substrates (PMID:17956988). Deacetylase activity measured in HDAC5 immunoprecipitates (PMID:10220385, PMID:10869435) co-purifies with HDAC3, and reconstitution shows that class II HDACs do not contribute to the activity of the SMRT/N-CoR-HDAC3 complex (PMID:11804585). The in vitro histone deacetylase activity is real but weak and of uncertain physiological relevance; HDAC5 represses chromatin mainly by recruiting HDAC3 complexes. Following the promiscuous-activity tiers, this is marked as an over-annotation rather than removed. Supporting Evidence: PMID:17956988 Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. PMID:17956988 A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. |
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Download this section (compressed HTML)Q: Does HDAC5 have a physiological substrate that its His-containing class IIa active site processes efficiently, or is all deacetylation attributed to HDAC5 (GCM1, tubulin) mediated by recruited HDAC3?
Q: GO:0000976 transcription cis-regulatory region binding is_a sequence-specific DNA binding; is it appropriate (even with contributes_to) for coregulators recruited by DNA-binding partners, as proposed in the HDAC4 review?
Q: Is HDAC5-mediated coactivation of HIF-1alpha seen at endogenous expression levels and in hypoxic tissues?
Experiment: Compare wild-type, catalytic-dead and His-to-Tyr (gain-of-activity) HDAC5 in HDAC5-null myoblasts and endothelial cells for repression of MEF2 targets and FGF2/SLIT2, with and without HDAC3 knockdown.
Hypothesis: Repression by HDAC5 does not need its own catalytic activity.
Type: genetic complementation
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