HSPA6 (also known as HSP70B') is a strictly stress-inducible member of the HSP70/HSPA molecular chaperone family. Unlike the constitutively expressed HSC70 or the basally expressed HSPA1A, HSPA6 shows no basal expression and is induced only at higher temperatures or under severe stress conditions (PMID:2327978). HSPA6 has the canonical HSP70 architecture: an N-terminal ATPase (nucleotide-binding) domain, a substrate- binding domain with a lid, and a C-terminal EEVD motif mediating co-chaperone interactions (DOI:10.3390/biom13040604). It functions as an ATP-dependent protein folding chaperone, cycling through ATP binding, hydrolysis, and ADP release to assist in protein folding and refolding, with J-domain proteins (HSP40/DNAJ) delivering clients and stimulating hydrolysis, and nucleotide exchange factors (BAG-family, HSPBP1, HSP110) promoting ADP release and client recycling (DOI:10.3390/biom13040604). In neuronal heat-stress models, HSPA6 is one of the most strongly induced HSP70 paralogs, showing approximately 13-14-fold induction under extreme heat vs approximately 2-3-fold under mild heat, with gene expression peaking at approximately 1 hour and protein at approximately 5-6 hours post-stress (DOI:10.3390/biology12030416). HSPA6 is co-expressed with key co-chaperones DNAJB1 (J-domain), BAG3 (NEF), and HSPH1/HSP110 (NEF) under stress, forming a coordinated inducible chaperone module for protein disaggregation and refolding (DOI:10.3390/biology12030416). Notably, HSPA6 displays substrate specificity distinct from other HSP70 family members; it cannot refold heat-denatured luciferase but can assist in reactivation of heat-unfolded p53, suggesting it has evolved to maintain specific critical functions under conditions of severe stress (PMID:21231916). HSPA6 has also been implicated in RTP1S-dependent trafficking of olfactory receptors, where co-expression of HSPA6 partially enhanced surface expression of an olfactory receptor by approximately 50-80%, interacting via its C-terminal domain with the RTP1S N-terminus (DOI:10.3390/ijms24097829). The HSPA6/HSP70B' promoter has been exploited in synthetic biology as a thermal gene switch for remote control of mammalian cells via photothermal activation (DOI:10.1021/acssynbio.7b00455).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation of GO:0005634 (nucleus) based on phylogenetic inference from HSP70 family orthologs. Multiple HSP70 family members are known to localize to the nucleus, and the phylogenetic evidence is broad, including yeast, worm, fly, and mammalian orthologs. CD-CODE database entries for HSPA6 (P17066) include nuclear speckle and nucleolus localizations, providing indirect support. However, direct experimental evidence for nuclear localization of HSPA6 is limited. Khalouei et al. (2014) used YFP-tagged HSPA6 in neuronal cells and primarily observed cytoplasmic and centriolar localization after heat stress (PMID:24061851). IBA annotations are generally reliable and this is plausible for an HSP70 family member. Reason: Nuclear localization is plausible by HSP70-family inference, but direct HSPA6-specific evidence is lacking in the available publications. The strongest HSPA6-specific localization evidence supports cytoplasmic and centriolar localization after heat stress, so nucleus should not be treated as a core HSPA6 location. Supporting Evidence: PMID:24061851 Stable lines of human SH-SY5Y neuronal cells were established that expressed YFP-tagged protein products of the human inducible HSP70 genes HSPA6 (HSP70B') and HSPA1A (HSP70-1) |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0005737 (cytoplasm) based on phylogenetic inference. This is strongly supported by direct experimental data: Khalouei et al. (2014) showed YFP-tagged HSPA6 localizes in the cytoplasm of human neuronal cells (PMID:24061851), and Hageman et al. (2011) showed cytosolic localization consistent with cytoplasmic distribution (PMID:21231916). Also supported by the IDA annotation from PMID:24061851. Reason: Cytoplasmic localization is a core feature of HSP70 family members and is directly supported by experimental IDA evidence from PMID:24061851 showing HSPA6-YFP in the cytoplasm of neuronal cells. The IBA is consistent with multiple lines of evidence. Supporting Evidence: PMID:24061851 YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation of GO:0005886 (plasma membrane) based on phylogenetic inference. Some HSP70 family members have been reported at the plasma membrane, particularly HSPA1A in cancer cells. There is no direct experimental evidence for HSPA6 at the plasma membrane in available publications. The IBA phylogenetic support includes several orthologs. While plasma membrane localization is documented for some family members, this may not be a core localization for the strictly stress-inducible HSPA6. Reason: Plasma membrane localization is documented for some HSP70 family members (e.g. HSPA1A in stressed/cancer cells), making the phylogenetic inference plausible. However, there is no direct evidence for HSPA6 at the plasma membrane and this is unlikely to be a core localization for this strictly stress-inducible member. The IBA is retained as non-core because the phylogenetic inference is reasonable but this is not experimentally validated for HSPA6. |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0016887 (ATP hydrolysis activity) based on phylogenetic inference across HSP70 family members. This is a core molecular function of HSPA6, directly confirmed by Hageman et al. (2011), who demonstrated that HSPA6 possesses intrinsic ATPase activity as high as that of canonical HSPA1A when stimulated by J-proteins (PMID:21231916). Also supported by IDA evidence from the same publication and IEA from InterPro domain mapping. Reason: ATP hydrolysis is the central catalytic activity of HSP70 family chaperones. HSPA6 ATPase activity is directly demonstrated experimentally (PMID:21231916). The IBA annotation is fully consistent with both the biochemical data and the conserved HSP70 domain architecture. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0031072 (heat shock protein binding) based on phylogenetic inference. This is directly supported by experimental IPI evidence from Hageman et al. (2011), who demonstrated physical interactions between HSPA6 and multiple J-domain co-chaperones (DNAJA1, DNAJA2, DNAJA4, DNAJB1, DNAJB4, DNAJB6, DNAJB2, and others) as well as co-chaperones like BAG1 and HSPBP1 (PMID:21231916). HSP70-J-protein interactions are central to the HSP70 chaperone cycle. Reason: HSP70 proteins functionally depend on interaction with J-domain co-chaperones (DNAJ proteins) and nucleotide exchange factors (BAG proteins, HSPBP1). Hageman et al. (2011) directly demonstrated these interactions for HSPA6 (PMID:21231916). The IBA is well-supported by experimental evidence and reflects a core aspect of HSP70 chaperone biology. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0044183 (protein folding chaperone) based on phylogenetic inference across HSP70 family members. This is the central molecular function of HSPA6. Hageman et al. (2011) demonstrated that purified HSPA6 can assist in reactivation of heat-unfolded p53, confirming active chaperone function (PMID:21231916). The ATPase activity and substrate-binding domain are functional. HSPA6 shows substrate specificity distinct from other HSP70 members (cannot refold luciferase but can refold p53), indicating a specialized chaperone role. Reason: Protein folding chaperone activity is the core evolved function of HSPA6 as an HSP70 family member. This is directly supported by experimental evidence showing HSPA6 can assist in reactivation of heat-unfolded p53 in an ATP-dependent manner (PMID:21231916). The IBA annotation correctly captures this core function. Supporting Evidence: PMID:21231916 purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53 file:human/HSPA6/HSPA6-deep-research-falcon.md HSPA6 is a prominent stress-inducible Hsp70 paralog whose chaperone role expands proteostasis capacity under proteotoxic stress. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0005829 (cytosol) based on phylogenetic inference. This is directly supported by IDA evidence from Hageman et al. (2011), who showed cytosolic localization of HSPA6 (PMID:21231916). Consistent with the known localization of most HSP70 family members. Reason: Cytosol is the primary localization for HSPA6 and most HSP70 family members. Directly supported by IDA evidence (PMID:21231916). The IBA annotation is consistent with experimental data. Supporting Evidence: PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of GO:0042026 (protein refolding) based on phylogenetic inference. Directly supported by experimental IDA evidence from Hageman et al. (2011), who showed HSPA6 can assist in reactivation (refolding) of heat-unfolded p53 (PMID:21231916). However, HSPA6 showed notably limited refolding capability compared to other HSP70 members -- it could not refold heat-denatured luciferase and could not suppress polyQ aggregation. The refolding function appears to be substrate-specific rather than general. Reason: Protein refolding is a core biological process for HSP70 chaperones. HSPA6 demonstrates refolding activity on at least one substrate (p53), although it shows substrate selectivity different from other family members (PMID:21231916). The IBA annotation is appropriate even though HSPA6 may have a narrower substrate range than other HSP70 members. Supporting Evidence: PMID:21231916 purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53 |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation of GO:0000166 (nucleotide binding) based on UniProtKB keyword mapping (KW-0547 Nucleotide-binding). This is a broad parent term. HSPA6 contains a well-characterized nucleotide-binding domain (NBD, residues 3-388) that binds ATP and ADP. The crystal structure of the ATPase domain (PDB:3FE1) confirms nucleotide binding (PMID:20072699). While correct, this is subsumed by the more specific ATP binding annotation. Reason: Nucleotide binding is correct for HSPA6 and is confirmed by crystal structure data (PDB:3FE1, PMID:20072699). Although this is a broader term than ATP binding, IEA annotations at a broader level than more specific annotations are acceptable. The UniProt keyword mapping is accurate. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of GO:0005524 (ATP binding) from combined automated annotation methods including InterPro domain mapping and UniProtKB keyword mapping. HSPA6 has a well-characterized ATP-binding domain (NBD, residues 3-388) with multiple ATP binding sites defined in UniProt (residues 14-17, 73, 204-206, 270-277, 341-344). The crystal structure of HSPA6 NBD in complex with ADP and phosphate (PDB:3FE1) directly confirms nucleotide binding (PMID:20072699). The original discovery paper (PMID:2327978) noted that HSP70B' protein bound ATP. Reason: ATP binding is a core biochemical property of HSPA6, confirmed by crystal structure (PDB:3FE1), biochemical assays (PMID:21231916), and the original characterization showing the protein binds ATP (PMID:2327978). The IEA is accurate and well-supported. Supporting Evidence: PMID:2327978 a more basic 70 kDa heat-shock protein that both the major stress-inducible HSP70 and constitutively expressed HSC70 heat-shock proteins, which in common with other heat-shock 70 kDa proteins bound ATP |
| GO:0006986 response to unfolded protein | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation of GO:0006986 (response to unfolded protein) generated by ARBA machine learning models. HSPA6 is a stress-inducible chaperone that is induced under severe stress conditions and participates in refolding of unfolded proteins (PMID:21231916). This annotation is consistent with the TAS annotation from PMID:2327978 for the same term. While HSPA6 is induced by heat stress rather than by unfolded proteins per se, the term is broadly appropriate for a heat shock protein that functions in protein quality control. Reason: Response to unfolded protein is appropriate for HSPA6 as a stress-inducible molecular chaperone that participates in refolding denatured proteins. Consistent with the TAS annotation for the same term from PMID:2327978. The IEA prediction is reasonable. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation of GO:0016887 (ATP hydrolysis activity) based on InterPro domain mapping (IPR013126 HSP70 family). HSPA6 contains the conserved HSP70 domain with ATPase activity, directly confirmed by Hageman et al. (2011), who showed HSPA6 has intrinsic ATPase activity as high as HSPA1A when stimulated by J-proteins (PMID:21231916). Also supported by IBA and IDA annotations for the same term. Reason: ATP hydrolysis activity is directly demonstrated for HSPA6 (PMID:21231916) and is correctly predicted from the HSP70 InterPro domain. The IEA is consistent with both IBA and IDA annotations for the same term. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation of GO:0019899 (enzyme binding) generated by ARBA machine learning models. HSPA6 interacts with METTL21A, a methyltransferase that trimethylates HSPA6 at Lys-563 (PMID:23921388). This makes the annotation technically correct. However, 'enzyme binding' is a vague term that does not convey informative molecular function. The more specific IPI annotation for the same term from PMID:23921388 captures the METTL21A interaction. The IEA adds no additional information. Reason: HSPA6 is a substrate of the methyltransferase METTL21A, so the interaction is real, but this reflects a modification event rather than HSPA6 performing enzyme binding as a core molecular function. The broad IEA should be kept only as a non-core interaction context. |
| GO:0042026 protein refolding | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation of GO:0042026 (protein refolding) generated by ARBA machine learning models. Consistent with IBA and IDA annotations for the same term. HSPA6 has been experimentally shown to assist in reactivation of heat-unfolded p53 (PMID:21231916), directly supporting this annotation. Reason: Protein refolding is directly demonstrated for HSPA6 (PMID:21231916). The IEA prediction is consistent with existing IBA and IDA annotations for the same term. |
| GO:0051082 unfolded protein binding | IEA GO_REF:0000117 | MODIFY | Summary: This IEA annotation of GO:0051082 (unfolded protein binding) was generated by ARBA machine learning models (GO_REF:0000117). GO:0051082 is now formally obsolete (go-ontology#30962) because it conflates passive binding with active chaperone function. HSPA6 is a well-characterized HSP70 family ATP-dependent chaperone. The annotation should be replaced with GO:0044183 (protein folding chaperone), which correctly represents the active chaperone function demonstrated experimentally for HSPA6 (PMID:21231916). This IEA annotation will likely be automatically updated when GO:0051082 is obsoleted, but should be modified to GO:0044183 regardless. Reason: GO:0051082 (unfolded protein binding) is scheduled for obsolescence (go-ontology#30962). HSPA6 functions as an ATP-dependent protein folding chaperone, not merely a passive binder of unfolded proteins. The ARBA-predicted annotation should be replaced with GO:0044183 (protein folding chaperone), consistent with the experimentally validated IDA evidence from PMID:21231916 showing HSPA6 assists in reactivation of heat-unfolded p53, and with the existing IBA annotation for GO:0044183. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53 |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | REMOVE | Summary: IPI annotation of GO:0005515 (protein binding) from Bouwmeester et al. (2004), a large-scale TAP-MS study mapping the TNF-alpha/NF-kappa B signaling pathway (PMID:14743216). HSPA6 (P17066) was identified as interacting with MAP3K14 (Q99558/NIK). This is a high-throughput interaction study; the interaction with MAP3K14 is recorded in IntAct. However, 'protein binding' is uninformative as a molecular function term. HSP70 chaperones interact with many proteins as part of their chaperone function, and this interaction likely reflects HSPA6 acting as a chaperone or being co-purified rather than a specific functional interaction. Reason: GO:0005515 (protein binding) is uninformative and does not convey specific molecular function. The interaction with MAP3K14 from a high-throughput TAP-MS study (PMID:14743216) likely reflects nonspecific chaperone-client or co-purification artifacts rather than a specific functional partnership. HSP70 proteins are well-known contaminants in affinity purification experiments. This annotation should be removed in favor of more informative terms like heat shock protein binding (GO:0031072) or protein folding chaperone (GO:0044183). Supporting Evidence: PMID:14743216 mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: IPI annotation of GO:0005515 (protein binding) from Lee et al. (2011), a genome-wide YFP fluorescence complementation (BiFC) screen for telomere regulators (PMID:21044950). HSPA6 was identified as interacting with TERF1 (P54274). This is a large-scale high-throughput screen examining ~12,000 human proteins. BiFC can trap transient or weak interactions but may also produce false positives due to irreversible YFP fragment complementation. The biological relevance of an HSPA6-TERF1 interaction is unclear. 'Protein binding' is uninformative. Reason: GO:0005515 (protein binding) is uninformative. The HSPA6-TERF1 interaction from a large-scale BiFC screen (PMID:21044950) is of uncertain biological significance. As the authors note, BiFC can trap weak/transient interactions and the identified proteins may associate under specific conditions or may be false positives. HSP70 chaperones interact broadly with client proteins and this likely represents nonspecific chaperone-client binding rather than a telomere-specific function. Supporting Evidence: PMID:21044950 transient or weak interactions as well as low abundance regulators that may be lost during in vitro purification steps, can be "trapped" thanks to the cofolding of YFP fragments |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: IPI annotation of GO:0005515 (protein binding) from Kennedy et al. (2020), a study on EGFR network rewiring in colorectal cancer cells expressing KRAS(G13D) (PMID:31980649). HSPA6 was identified as interacting with MAP3K14 (Q99558) in this proteomics study. This is a large-scale interaction study; HSP70 proteins are commonly identified as interactors in such studies due to their chaperone function. 'Protein binding' is uninformative. Reason: GO:0005515 (protein binding) is uninformative. The interaction detected in a large-scale network study (PMID:31980649) likely reflects HSPA6 chaperone activity on client proteins rather than a specific functional interaction. HSP70 proteins are frequently detected in interactome studies as nonspecific interactors or chaperone-client pairs. Supporting Evidence: PMID:31980649 Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS) |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI annotation of GO:0005515 (protein binding) from Luck et al. (2020), the Human Reference Interactome (HuRI) systematic yeast two-hybrid binary interactome mapping (PMID:32296183). Multiple interactions were detected for HSPA6 including with AHCYL1 (O43865), BAG4 (O95429), FLNA (P21333-2), PPIB (P23284), RPA1 (P27694), LGALS7B (P47929), COMMD6 (Q7Z4G1), KRT222 (Q8N1A0), C22orf15 (Q8WYQ4-2), and PRAP1 (Q96NZ9). The BAG4 interaction is notable as BAG proteins are known nucleotide exchange factors for HSP70 chaperones and this interaction is biologically meaningful. However, 'protein binding' is uninformative. The BAG4 interaction would be better annotated under heat shock protein binding (GO:0031072). Reason: GO:0005515 (protein binding) is uninformative. While some interactions from HuRI may be biologically relevant (e.g., BAG4 as a nucleotide exchange factor), the generic 'protein binding' term does not capture this specificity. HSP70 proteins interact broadly with many partners through their chaperone function. The BAG4 interaction is already better captured by the heat shock protein binding annotation (GO:0031072). The remaining interactions are likely chaperone-client interactions or Y2H artifacts. Supporting Evidence: PMID:32296183 HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes |
| GO:0016887 ATP hydrolysis activity | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: IDA annotation of GO:0016887 (ATP hydrolysis activity) from Hageman et al. (2011). This study directly demonstrated that HSPA6 possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins (PMID:21231916). This is high-quality direct experimental evidence for a core molecular function of HSPA6. Reason: This is well-supported IDA evidence for a core molecular function. Hageman et al. (2011) directly measured HSPA6 ATPase activity and showed it is comparable to HSPA1A when stimulated by J-proteins (PMID:21231916). ATP hydrolysis is central to the HSP70 chaperone cycle and represents a core function of HSPA6. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: TAS annotation of GO:0005576 (extracellular region) from Reactome pathway R-HSA-6798748 (Exocytosis of secretory granule lumen proteins). This annotation indicates HSPA6 is found in the extracellular space, presumably after release from neutrophil secretory granules. HSP70 proteins can be released extracellularly, particularly from immune cells. This is a plausible but non-core localization for HSPA6, which primarily functions as an intracellular chaperone. Reason: Extracellular release of HSP70 family members from neutrophil granules is documented. However, this is not a core localization for HSPA6, which primarily functions as an intracellular stress-inducible chaperone. The Reactome pathway annotation is retained as non-core. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: TAS annotation of GO:0005576 (extracellular region) from Reactome pathway R-HSA-6800434 (Exocytosis of ficolin-rich granule lumen proteins). Same rationale as the R-HSA-6798748 annotation above -- HSPA6 may be released extracellularly from neutrophil granules, but this is not a core localization. Reason: Duplicate extracellular region annotation from a different Reactome pathway (ficolin-rich granule exocytosis). Same rationale as R-HSA-6798748: extracellular release is plausible but not a core localization for this intracellular chaperone. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: TAS annotation of GO:0034774 (secretory granule lumen) from Reactome pathway R-HSA-6798748 (Exocytosis of secretory granule lumen proteins). This indicates HSPA6 is found in neutrophil secretory granule lumens. HSP70 proteins have been detected in neutrophil granules. This is a specialized localization for an immune cell context, not a core localization for HSPA6. Reason: Localization to neutrophil secretory granule lumen is plausible based on Reactome curation of neutrophil degranulation pathways. However, this is a specialized immune cell context and not a core localization for HSPA6, which primarily functions as a cytosolic stress-inducible chaperone. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: TAS annotation of GO:1904813 (ficolin-1-rich granule lumen) from Reactome pathway R-HSA-6800434 (Exocytosis of ficolin-rich granule lumen proteins). This is a specific sub-type of neutrophil granule. Similar rationale to the secretory granule lumen annotation -- this is a specialized immune cell localization. Reason: Ficolin-1-rich granule lumen is a specific neutrophil granule compartment. While plausible based on Reactome curation, this represents a specialized immune cell context rather than a core localization for the stress-inducible cytosolic chaperone HSPA6. |
| GO:0005814 centriole | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: IDA annotation of GO:0005814 (centriole) from Khalouei et al. (2014), who demonstrated that YFP-tagged HSPA6 rapidly localizes to centrioles in human SH-SY5Y neuronal cells following thermal stress (PMID:24061851). HSPA6 showed more prolonged centriolar localization than HSPA1A and specifically targeted the proximal end of centrioles (identified by gamma-tubulin marker). The authors suggest this indicates the proximal end of centrioles may be a stress-sensitive site in neurons. Reason: This is well-supported IDA evidence showing stress-induced centriolar localization in neuronal cells (PMID:24061851). The localization was confirmed using YFP-tagged HSPA6 and co-localization with centrosome markers. The prolonged localization at centrioles compared to HSPA1A suggests a specific stress- protective role at this structure. Supporting Evidence: PMID:24061851 YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells, with HSPA6 demonstrating a more prolonged signal compared to HSPA1A PMID:24061851 The YFP-tagged HSP70 proteins targeted the proximal end of centrioles (identified by gamma-tubulin marker) rather than the distal end (centrin marker) |
| GO:0034605 cellular response to heat | IMP PMID:21597468 Transformation of eEF1BΞ΄ into heat-shock response transcript... | ACCEPT | Summary: IMP annotation of GO:0034605 (cellular response to heat) from Kaitsuka et al. (2011) (PMID:21597468). This paper is about eEF1Bdelta (a translation elongation factor), not directly about HSPA6. The paper describes how eEF1BdeltaL induces HSE-containing genes including HSP70 genes in cooperation with HSF1. HSPA6 as a heat-inducible gene is expected to be among the targets induced. The connection to HSPA6 in this IMP annotation may derive from HSPA6 being used as a reporter or marker of the heat shock response. As an HSP70 gene strictly induced by heat stress, HSPA6 is clearly involved in cellular response to heat. Reason: HSPA6 is a strictly heat-inducible gene that shows no basal expression and is only expressed under severe thermal stress (PMID:2327978). Cellular response to heat is a core biological process for HSPA6. While PMID:21597468 focuses on eEF1BdeltaL, HSPA6 involvement in the heat shock response is well-established and supported by multiple references. Supporting Evidence: PMID:2327978 HSP70B' mRNA was induced only at higher temperature and showed no basal expression |
| GO:0019899 enzyme binding | IPI PMID:23921388 Identification and characterization of a novel human methylt... | KEEP AS NON CORE | Summary: IPI annotation of GO:0019899 (enzyme binding) from Jakobsson et al. (2013), who identified METTL21A (Q8WXB1) as the methyltransferase responsible for trimethylation of HSPA6 at Lys-563 (PMID:23921388). HSPA6 is a substrate of METTL21A, so this interaction is well-characterized. However, the term 'enzyme binding' is somewhat vague. In this case, HSPA6 is the substrate of the methyltransferase, so the interaction is real and specific, but it reflects HSPA6 being modified rather than performing enzyme binding as a molecular function. Reason: The interaction between HSPA6 and METTL21A is directly demonstrated with biochemical evidence showing METTL21A trimethylates HSPA6 at Lys-563 (PMID:23921388). The annotation reflects a validated physical interaction with the methyltransferase, but HSPA6 is a substrate in this context rather than an enzyme-binding factor, so this is non-core. Supporting Evidence: PMID:23921388 we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins |
| GO:0031072 heat shock protein binding | IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: IPI annotation of GO:0031072 (heat shock protein binding) from Hageman et al. (2011) (PMID:21231916). The GOA data shows interactions with multiple co-chaperones including DNAJA2 (O60884), DNAJB1 (P25685), DNAJB4 (Q9UDY4), DNAJB6 (O75190), DNAJB2 (P25686), DNAJA1 (P31689), DNAJA4 (Q8WW22), and others (Q7Z6W7/DNAJB12, Q8NHS0/DNAJB14). These are J-domain proteins (HSP40 family) that function as co-chaperones essential for the HSP70 chaperone cycle. This is a core molecular function for HSPA6. Reason: HSP70-J-protein (HSP40/DNAJ) interactions are essential for the HSP70 chaperone cycle. Hageman et al. (2011) directly demonstrated HSPA6 interactions with multiple J-domain co-chaperones including DNAJA1, DNAJA2, DNAJA4, DNAJB1, DNAJB2, DNAJB4, DNAJB6, and others (PMID:21231916). These interactions stimulate HSPA6 ATPase activity, confirming functional relevance. This is a core function annotation. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins |
| GO:0042026 protein refolding | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: IDA annotation of GO:0042026 (protein refolding) from Hageman et al. (2011). The authors directly demonstrated that purified HSPA6 can assist in reactivation of heat-unfolded p53 in vitro (PMID:21231916). Notably, HSPA6 showed restricted substrate specificity -- it could not refold heat-denatured luciferase and could not suppress polyQ aggregation, unlike HSPA1A. This IDA evidence directly supports protein refolding activity with specific substrate selectivity. Reason: Direct experimental evidence from in vitro refolding assays demonstrates HSPA6 can refold heat-unfolded p53 (PMID:21231916). This is high-quality IDA evidence for a core biological process of HSPA6. The substrate specificity (p53 but not luciferase) highlights that HSPA6 has evolved specialized refolding function. Supporting Evidence: PMID:21231916 purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53 |
| GO:0051082 unfolded protein binding | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | MODIFY | Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). HSPA6 is an HSP70 family member that functions as an ATP-dependent foldase chaperone, not merely a passive binder of unfolded proteins. Hageman et al. (2011) demonstrated that HSPA6 has a functional substrate-binding domain and intrinsic ATPase activity, and that purified HSPA6 could assist in reactivation of heat-unfolded p53 (PMID:21231916). These data support annotation to GO:0044183 (protein folding chaperone), which captures the active chaperone mechanism. The IBA annotation for GO:0044183 already exists for HSPA6 via phylogenetic inference, consistent with this replacement. Reason: GO:0051082 (unfolded protein binding) is scheduled for obsolescence (go-ontology#30962) because it conflates passive binding of unfolded proteins with active chaperone function. HSPA6 is a bona fide ATP-dependent molecular chaperone of the HSP70 family. The original IDA evidence from PMID:21231916 demonstrates that HSPA6 possesses intrinsic ATPase activity stimulated by J-proteins and can assist in reactivation of heat-unfolded p53, which constitutes active chaperone function rather than mere unfolded protein binding. The correct replacement term is GO:0044183 (protein folding chaperone), defined as "Binding to a protein or a protein-containing complex to assist the protein folding process." This term is already applied to HSPA6 via IBA (GO_REF:0000033). Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins PMID:21231916 purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53 |
| GO:0070370 cellular heat acclimation | IMP NOT PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: NOT annotation for GO:0070370 (cellular heat acclimation) from Hageman et al. (2011) (PMID:21231916). The authors showed that siRNA-mediated blocking of HSPA6 did not impair the development of heat-induced thermotolerance, and that overexpression of HSPA6 did not protect cells from heat-induced cell death (unlike HSPA1A). This negative result is informative and demonstrates that despite being heat-inducible, HSPA6 does not contribute to acquired thermotolerance, distinguishing it functionally from HSPA1A. Reason: This is a well-supported NOT annotation based on direct experimental evidence. Hageman et al. (2011) demonstrated via both loss-of-function (siRNA knockdown) and gain-of-function (overexpression) experiments that HSPA6 does not contribute to cellular heat acclimation/thermotolerance (PMID:21231916). This negative annotation is informative and functionally distinguishes HSPA6 from HSPA1A. Supporting Evidence: PMID:21231916 whereas overexpression of HSPA1A protected cells from heat-induced cell death, overexpression of HSPA6 did not PMID:21231916 siRNA (small interfering RNA)-mediated blocking of HSPA6 did not impair the development of heat-induced thermotolerance |
| GO:0005737 cytoplasm | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: IDA annotation of GO:0005737 (cytoplasm) from Khalouei et al. (2014). Using YFP-tagged HSPA6 in stable human SH-SY5Y neuronal cell lines, the authors observed HSPA6 in the cytoplasm following thermal stress (PMID:24061851). This is consistent with the IBA annotation for the same term and with the known cytoplasmic localization of HSP70 family members. Reason: Direct experimental evidence using YFP-tagged HSPA6 confirms cytoplasmic localization in human neuronal cells (PMID:24061851). Cytoplasm is a core localization for HSPA6. Consistent with IBA annotation. Supporting Evidence: PMID:24061851 YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells |
| GO:0005829 cytosol | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: IDA annotation of GO:0005829 (cytosol) from Hageman et al. (2011). The study establishes HSPA6 as a cytosolic HSP70 family member (PMID:21231916). Most HSP70/HSPA family members are cytosolic, and HSPA6 is described as such in this study. Consistent with the IBA annotation for the same term. Reason: Cytosol is the primary localization for HSPA6 as established in PMID:21231916. This is consistent with the general cytosolic localization of HSP70 family members and with the IBA annotation. Core localization for HSPA6. Supporting Evidence: PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol |
| GO:0034605 cellular response to heat | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: IDA annotation of GO:0034605 (cellular response to heat) from Khalouei et al. (2014). The authors showed that HSPA6 rapidly localizes to centrioles in human neuronal cells following thermal stress (PMID:24061851). HSPA6 is a strictly heat-inducible gene with no basal expression (PMID:2327978), and its rapid stress-induced relocalization to centrioles is a direct cellular response to heat. Reason: HSPA6 is a strictly heat-inducible chaperone and its stress-induced localization to centrioles directly demonstrates cellular response to heat (PMID:24061851). Combined with the original characterization showing no basal expression and induction only at higher temperatures (PMID:2327978), cellular response to heat is a core process for HSPA6. Supporting Evidence: PMID:24061851 Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells PMID:2327978 HSP70B' mRNA was induced only at higher temperature and showed no basal expression |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | KEEP AS NON CORE | Summary: HDA annotation of GO:0072562 (blood microparticle) from Bastos-Amador et al. (2012), a proteomic analysis of microvesicles from plasma of healthy donors (PMID:22516433). HSPA6 was detected in blood microparticles by mass spectrometry. This is a high-throughput proteomics identification. HSP70 proteins are commonly found in extracellular vesicles, but this is not a core localization for HSPA6, which is primarily an intracellular stress-inducible chaperone. Reason: Detection of HSPA6 in blood microparticles by HDA proteomics (PMID:22516433) is plausible given that HSP70 proteins are commonly found in extracellular vesicles. However, this is not a core localization for HSPA6. The annotation is retained as non-core. Note that HSP70 proteins are common contaminants in proteomic studies. Supporting Evidence: PMID:22516433 We have detected 161 microvesicle-associated proteins, including many associated with the complement and coagulation signal-transduction cascades |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: HDA annotation of GO:0070062 (extracellular exosome) from Gonzalez-Begne et al. (2009), a proteomic analysis of human parotid gland exosomes by MudPIT mass spectrometry (PMID:19199708). HSPA6 was identified among 491 exosomal proteins. HSP70 family proteins (including HSC70/HSPA8) are well-established exosome markers, so detection of HSPA6 is not surprising. However, this may reflect co-purification with other more abundant HSP70 family members, especially since HSPA6 has no basal expression and would not be expected in normal parotid exosomes unless the cells were stressed. Reason: HSPA6 detection in exosomes (PMID:19199708) is plausible but raises questions given that HSPA6 has no basal expression (PMID:2327978). This may reflect cross-identification with other HSP70 family members given high sequence similarity, or the cells may have been under stress. HSP70 family members are common exosome cargo. Retained as non-core since extracellular exosome is not a core localization for HSPA6. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva |
| GO:0008180 COP9 signalosome | IDA PMID:18850735 Characterization of the human COP9 signalosome complex using... | MARK AS OVER ANNOTATED | Summary: IDA annotation of GO:0008180 (COP9 signalosome) from Fang et al. (2008), who performed proteomic characterization of the human COP9 signalosome using affinity purification and mass spectrometry (PMID:18850735). The GOA data shows this annotation uses the qualifier 'colocalizes_with' rather than 'is_active_in', indicating HSPA6 was found co-localizing with the COP9 signalosome rather than being a core component. HSPA6 was likely identified as one of 52 putative CSN interacting proteins. HSP70 proteins are commonly identified in affinity purification experiments as chaperone-client interactions or co-purification artifacts. Reason: HSPA6 was identified as co-localizing with the COP9 signalosome in a high-throughput AP-MS study (PMID:18850735). HSP70 chaperones are well-known co-purification contaminants in affinity purification experiments. The colocalizes_with qualifier is appropriate (not a core CSN component), but this likely represents a transient chaperone-client interaction rather than meaningful co-localization with the COP9 signalosome. This is an over-annotation of what is probably a non-specific interaction. Supporting Evidence: PMID:18850735 A total of 52 putative human CSN interacting proteins were identified, most of which are reported for the first time |
| GO:0006986 response to unfolded protein | TAS PMID:2327978 The human heat-shock protein family. Expression of a novel h... | ACCEPT | Summary: TAS annotation of GO:0006986 (response to unfolded protein) from Leung et al. (1990), the original paper characterizing HSPA6/HSP70B' (PMID:2327978). The paper showed that HSPA6 is a heat-inducible HSP70 family member with no basal expression, induced only at higher temperatures. As a stress-inducible molecular chaperone of the HSP70 family, HSPA6 participates in the cellular response to unfolded/denatured proteins generated by heat stress. The annotation is appropriate, though the direct connection to unfolded protein specifically (rather than heat stress generally) requires inference from the HSP70 function. Reason: HSPA6 is a heat-inducible HSP70 molecular chaperone (PMID:2327978) that functions in refolding denatured proteins (PMID:21231916). The response to unfolded protein annotation is appropriate because HSPA6 is induced under conditions that generate unfolded proteins (heat stress) and directly participates in their refolding. The TAS evidence from the original characterization paper is reasonable. Supporting Evidence: PMID:2327978 HSP70B' mRNA was induced only at higher temperature and showed no basal expression |
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