HSPH1 (Hsp105/Hsp110) is a stress-inducible, abundant cytosolic member of the Hsp110 branch of the Hsp70 superfamily. It has an Hsp70-like nucleotide-binding domain and a substrate-binding domain with a long acidic insertion and an extended C-terminal region. Its established molecular function is that of a nucleotide-exchange factor for cytosolic Hsp70s (HSPA1A, HSPA1B and HSPA8). HSPH1 binds the Hsp70 nucleotide-binding domain and accelerates ADP release, which triggers client release and so paces the Hsp70/J-protein folding cycle. With Hsp70 and J-proteins it promotes refolding of denatured proteins and dissolution of protein aggregates. In human cytosol the related Hsp110 HSPA4 (Apg-2) makes the larger contribution to aggregate dissolution. Mammalian HSPH1 orthologs can also hold heat-denatured proteins in a soluble, folding-competent state and protect cells from heat stress. Its own ATP hydrolysis is weak or absent. HSPH1 is induced by heat and other stresses. An alternatively spliced beta isoform lacking 44 residues is induced only by heat shock. An exon-9-skipped mutant (HSP110deltaE9) that lacks the substrate-binding domain occurs in microsatellite-unstable colorectal cancer and acts as a dominant-negative inhibitor of HSPH1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000774 adenyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER node PTN002900795, seeded by yeast and Candida Hsp110/Grp170 proteins and by human HSPH1 itself. Nucleotide exchange on Hsp70 is the defining activity of the Hsp110 clade. Reason: HSPH1 (PTHR45639:SF2) sits inside the Hsp110 clade that PAINT placed this activity on. HSPH1 also has direct experimental evidence for the activity (Rauch and Gestwicki; Dragovic et al.), and its own appearance among the IBD seeds shows that grounding. This is the core molecular function. Supporting Evidence: PMID:16688212 Furthermore, we found NEF activity on Hsp70 for human Hsp110, which is more distantly related to Sse1p (39% identity). PMID:24318877 All of the NEFs competed for binding to Hsp70, and their relative affinity values predicted their potency in nucleotide and peptide release assays. |
| GO:0000774 adenyl-nucleotide exchange factor activity | IDA PMID:24318877 Binding of human nucleotide exchange factors to heat shock p... | ACCEPT | Summary: Rauch and Gestwicki measured binding of human HSPA1A to BAG1-3 and to Hsp105 (HSPH1). Binding affinities predicted potency in nucleotide-release and peptide-release assays. Reason: Direct biochemical evidence with purified human proteins, corroborated by the human Hsp110 MABA-ADP release data of Dragovic et al. and by the UniProt curated function. This is the core function. Supporting Evidence: PMID:24318877 we measured the binding of human Hsp72 (HSPA1A) to BAG1, BAG2, BAG3, and the unrelated NEF Hsp105 PMID:16688212 the dissociation rate constant of MABA-ADP was increased file:human/HSPH1/HSPH1-uniprot.txt Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release (PubMed:24318877). |
| GO:0005515 protein binding | IPI PMID:17024176 A novel HSF1-mediated death pathway that is suppressed by he... | REMOVE | Summary: Interaction with mouse Tdag51 (Phlda1). Hsps were reported to bind the N-terminal PH-like domain of Tdag51 and suppress its pro-death activity. Reason: Generic protein binding is uninformative. The cached record is abstract-only and does not say which Hsps or which assay, so no more specific function can be derived. Removal does not dispute the interaction. Suppression of Tdag51-mediated death is not established as a core HSPH1 activity. Supporting Evidence: PMID:17024176 Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of Tdag51, and suppressed death activity of the C-terminal proline/glutamine/histidine-rich domain. |
| GO:0005515 protein binding | IPI PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | REMOVE | Summary: Co-purification with the Hsp70 lysine methyltransferase METTL21A in an AP-MS study of methyltransferase interactomes. Reason: Generic protein binding is uninformative. METTL21A co-purified with Hsp70 isoforms and Hsp110s, which is consistent with HSPH1 being recovered as part of Hsp70 complexes rather than as a direct, functionally characterised METTL21A partner. No more specific MF is supported. Removal does not dispute the co-purification. Supporting Evidence: PMID:23349634 METTL21A, the only known Hsp70 methyltransferase identified so far, copurified with a number of Hsp70 isoforms but few cofactors aside from Hsp110s. |
| GO:0005515 protein binding | IPI PMID:24318877 Binding of human nucleotide exchange factors to heat shock p... | MODIFY | Summary: Direct binding of HSPH1 to HSPA1A (Hsp72), measured with purified proteins as part of the NEF competition study. Reason: The interaction is with an Hsp70 and is the basis of the NEF activity, so GO:0030544 Hsp70 protein binding captures it informatively. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:24318877 we measured the binding of human Hsp72 (HSPA1A) to BAG1, BAG2, BAG3, and the unrelated NEF Hsp105 file:human/HSPH1/HSPH1-uniprot.txt Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). |
| GO:0005515 protein binding | IPI PMID:24318877 Binding of human nucleotide exchange factors to heat shock p... | MODIFY | Summary: Binding of HSPH1 to HSPA1B, which has the same mature sequence as HSPA1A. Reason: Same evidence as the HSPA1A row. It is an Hsp70 interaction underlying NEF activity, so it is better captured as Hsp70 protein binding. Proposed replacements: Hsp70 protein binding Supporting Evidence: file:human/HSPH1/HSPH1-uniprot.txt Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | MODIFY | Summary: Interaction from the Taipale et al. quantitative chaperone network. The partner Q96BE0 is an unreviewed fragment of the constitutive Hsp70 HSC70 (HSPA8). Hsp70 NEFs were among the baits. Reason: The partner is an Hsp70 (HSPA8 fragment), and HSPH1 interacts with HSPA8 as an NEF (UniProt, by similarity to rodent orthologs). Hsp70 protein binding is the informative term. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:25036637 First, we cloned all previously identified and characterized Hsp90 co-chaperones and Hsp70 nucleotide-exchange factors. file:human/HSPH1/HSPH1-uniprot.txt Interacts with HSPA8/HSC70 (By similarity). |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO from the Hsp70 family signature. HSPH1 retains the Hsp70-type nucleotide-binding domain. In the Hsp110 mechanism, ATP-bound Hsp110 forms the nucleotide-exchange complex with Hsp70. Reason: ATP binding by the NBD is part of how Hsp110s work, but the structural evidence is for yeast Hsp110 with bovine Hsc70, not human HSPH1. Here ATP binding supports the NEF activity and is not a function in its own right. The term is correct at family level and kept as non-core. Supporting Evidence: PMID:18550409 Binding of ATP to Hsp110 induces the closed conformation, which can then bind Hsc70 and induce the latter to open, facilitating nucleotide release. |
| GO:0005576 extracellular region | TAS PMID:12952910 Come forth CD1d: Hsp110 in the regulation of intestinal epit... | KEEP AS NON CORE | Summary: The commentary discusses Hsp110 recovered from intestinal luminal contents, presumed to be released from epithelium. It notes that Hsp110 has no signal peptide. Reason: Extracellular Hsp110 has been detected, but the release route is unknown and probably non-canonical or due to cell turnover. The main site of action is the cytosol, so this is kept as a non-core location. Supporting Evidence: PMID:12952910 Yet, Hsp110 does not possess a signal peptide and so cannot be secreted from IECs via the classical secretory pathway. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2247514 | KEEP AS NON CORE | Summary: Reactome places HSPH1 as an extracellular ligand of the scavenger receptor SCARF1 before endocytosis. Reason: Consistent with the other extracellular-region row. Exogenous or released HSPH1 can act as a scavenger-receptor ligand, but this is peripheral to its intracellular chaperone function. Supporting Evidence: Reactome:R-HSA-2247514 The SCARF1:ligand complex is endocytosed |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the eukaryotic Hsp110 node PTN000452854, seeded by Arabidopsis Hsp110 and by mouse and human HSPH1. Reason: Nuclear HSPH1 is supported by HPA immunofluorescence (nucleoplasm) and by the IBA seeds. The human cloning study, however, found HSPH1 mainly cytoplasmic and absent from nucleoli. There is no specific nuclear activity for HSPH1, so this is a secondary location. Supporting Evidence: PMID:9931472 hsp105 was present in the cytoplasm but was not found in the nucleoli of mammalian cells under both nonstressed and stressed conditions |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localization to the nucleoplasm, alongside cytosol. Reason: Curated immunofluorescence evidence that I accept. It fits with the IBA nucleus row and with the absence of HSPH1 from nucleoli reported by Ishihara et al. It is secondary to the cytosolic site of NEF function. Supporting Evidence: PMID:9931472 hsp105 was present in the cytoplasm but was not found in the nucleoli |
| GO:0005737 cytoplasm | IDA PMID:9931472 Molecular cloning, expression and localization of human 105 ... | ACCEPT | Summary: An antibody against recombinant human hsp105alpha showed cytoplasmic localization by immunofluorescence in unstressed and stressed cells. Reason: Direct human evidence. Immunofluorescence at this resolution supports cytoplasm, and cytosol is captured by the HPA, IBA and Hageman et al. rows. Supporting Evidence: PMID:9931472 hsp105 was present in the cytoplasm but was not found in the nucleoli of mammalian cells under both nonstressed and stressed conditions |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping from the UniProt subcellular-location annotation Cytoplasm, which is itself based on PMID:9931472. Reason: Consistent with the IDA row for the same term. Supporting Evidence: PMID:9931472 hsp105 was present in the cytoplasm |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the eukaryotic Hsp110 node PTN000452854. Seeds include human HSPH1, HSPA4 and HSPA4L. Reason: Hsp110s are cytosolic Hsp70 NEFs, and HSPH1 has its own experimental cytosol evidence. This is the site of the core function. Supporting Evidence: PMID:16364315 exclusively found in the cytosol of eukaryotic organisms |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localization to the cytosol. Reason: Consistent with all other localization evidence. Cytosol is where HSPH1 acts as an Hsp70 NEF. Supporting Evidence: PMID:9931472 hsp105 was present in the cytoplasm |
| GO:0005829 cytosol | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. surveyed the cytosolic HSPA/HSPH and DNAJ members of the human HSP70 machine in overexpression assays. Reason: The cached record is abstract-only, but it states that most of the HSPs examined are cytosolic. This agrees with the other evidence, and I defer to the curator for the HSPH1-specific observation. Supporting Evidence: PMID:21231916 most of the corresponding proteins are localized in the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252079 | ACCEPT | Summary: Reactome reaction in which cytosolic HSP110s exchange ATP for ADP on HSP70s. Reason: Consistent with the experimental cytosol rows and the NEF function. Supporting Evidence: Reactome:R-HSA-5252079 Eukaryote NEFs include heat-shock protein 105kDa (HSPH1 aka HSP110) |
| GO:0005874 microtubule | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from the mouse 1:1 ortholog Hsph1 (Q61699, also PTHR45639:SF2). Its source is an IDA showing that Hsp105alpha colocalizes with microtubules [PMID:12749852]. Reason: The orthology is sound (same PANTHER subfamily SF2). The source observation is a single immunofluorescence colocalization, interpreted as protection of microtubules under stress. It has not been shown for human HSPH1 and is peripheral to NEF function. Kept as non-core. Supporting Evidence: PMID:12749852 Indirect immunofluorescence analysis with anti-Hsp105 and anti-alpha-tubulin antibodies indicated that Hsp105alpha was colocalized with microtubules. |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the eukaryotic Hsp110 node, seeded by yeast Sse1/Sse2, Candida Msi3, mouse Hsph1 and worm Hsp110. Reason: HSPH1 takes part in Hsp70-mediated folding because its nucleotide exchange paces client release in each cycle. Human Hsp110 (HspH1) increased Hsp70/Hsp40-dependent luciferase refolding [PMID:16688212]. The Hsp110 node assigns protein folding at this level and does not assign the family-root Hsp70 chaperone or ATP hydrolysis activities. That boundary is respected here. Supporting Evidence: PMID:16688212 Analogous experiments were also performed using the human homologues, Hsp70 and Hsp110 (HspH1) PMID:16688212 Here, we show that members of the Hsp70-related Hsp110 family cooperate with Hsp70 in protein folding in the eukaryotic cytosol. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA machine-learning assignment of the generic stress-response term. Reason: HSPH1 is stress-inducible and acts in proteotoxic stress, so the term is true, but it adds nothing beyond the more specific response to unfolded protein row in this review. Supporting Evidence: PMID:9931472 The transcript of pBH105-1 was induced by various stresses in HeLa cells |
| GO:0006986 response to unfolded protein | TAS PMID:9931472 Molecular cloning, expression and localization of human 105 ... | KEEP AS NON CORE | Summary: The human HSPH1 cloning paper reports induction of the alpha transcript by various stresses and of the beta isoform by 42 °C heat shock. Reason: HSPH1 is a stress-inducible component of the cytosolic chaperone network that copes with unfolded proteins. Mammalian Hsp110 protects heat-denatured proteins and confers thermoresistance [PMID:9395504]. The term is acceptable, but it describes the cellular response that HSPH1 is induced in, not its specific activity (Hsp70 nucleotide exchange in folding), so it is kept as non-core. Supporting Evidence: PMID:9931472 The transcript of pBH105-1 was induced by various stresses in HeLa cells PMID:9395504 It was observed that the overexpression in vivo of hsp110 conferred substantial heat resistance to both Rat-1 and HeLa cells. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO transfer of ATPase activity from the Hsp70 family signature. Reason: Canonical Hsp70s hydrolyse ATP, but Hsp110s have diverged. Hsp105alpha/beta showed no ATPase activity in one study [PMID:10860841], and Hsp110-driven disaggregation depends on nucleotide exchange rather than ATPase activity [PMID:22990239]. PAINT placed ATP hydrolysis activity on the canonical family node (PTN000452648) but did not propagate it to the Hsp110 clade that HSPH1 belongs to. I treat that as a deliberate curator decision. Some weak intrinsic ATPase may exist (as reported for human Apg-2/HSPA4 [PMID:16364315]), so this is marked as over-annotation rather than removed. Supporting Evidence: PMID:10860841 although Hsp105alpha and Hsp105beta did not show ATPase activity PMID:22990239 This Hsp110 effect relies on nucleotide exchange, not on ATPase activity, implying ATP-driven chaperoning is not required. |
| GO:0032991 protein-containing complex | IDA PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | KEEP AS NON CORE | Summary: HSPH1 co-purified in METTL21A-containing Hsp70 complexes by AP-MS. Reason: HSPH1 does form stable complexes with Hsp70s, so the claim is correct. GO has no specific Hsp110:Hsp70 complex term to refine it to. It is uninformative and non-core. Supporting Evidence: PMID:23349634 copurified with a number of Hsp70 isoforms but few cofactors aside from Hsp110s |
| GO:0043014 alpha-tubulin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Hsph1 (same PANTHER subfamily SF2), whose IDA comes from a yeast two-hybrid screen and in vitro/in vivo binding of Hsp105alpha to alpha-tubulin [PMID:12749852]. Reason: The orthology supports the transfer, and the source experiment reports direct binding. The physiological role (protecting microtubules under heat stress) comes from one lab and has not been shown in human. It is not part of the core NEF function. Supporting Evidence: PMID:12749852 Hsp105alpha bound directly to alpha-tubulin both in vitro and in vivo. |
| GO:0045345 positive regulation of MHC class I biosynthetic process | TAS PMID:12952910 Come forth CD1d: Hsp110 in the regulation of intestinal epit... | MARK AS OVER ANNOTATED | Summary: The commentary reports that recombinant Hsp110 added to colonic epithelial cell lines increased surface expression of CD1d, a nonclassical MHC class I-like molecule. Reason: The observation is a single study of exogenous recombinant protein raising surface CD1d on cultured cells. It measured surface expression, not biosynthesis, and the mechanism is unknown. The commentary itself frames autocrine regulation as an open question. Contaminant effects of recombinant Hsps cannot be excluded, and nothing shows that endogenous HSPH1 regulates MHC class I production. Supporting Evidence: PMID:12952910 Might this abundant chaperone serve an autocrine function in the regulation of CD1d expression? |
| GO:0051135 positive regulation of NK T cell activation | TAS PMID:12952910 Come forth CD1d: Hsp110 in the regulation of intestinal epit... | REMOVE | Summary: The commentary speculates that luminal Hsp110 could induce CD1d and thereby activate NK T cells. Reason: The cited commentary presents NK T cell activation only as a hypothesis ("perhaps") downstream of CD1d induction. No experiment there shows that HSPH1 regulates NK T cell activation. At most this would be an indirect downstream effect, not participation. Supporting Evidence: PMID:12952910 a subsequent activation of NK T cells, and IL-13 |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: HSPH1 detected among 539 proteins in the proteome of B-cell-derived exosomes. Reason: High-throughput proteomic detection. Abundant cytosolic chaperones are commonly found in exosomes. The detection is plausible but has no known functional significance. Supporting Evidence: PMID:20458337 identified 539 proteins, including known and not previously identified constituents |
| GO:0071682 endocytic vesicle lumen | TAS Reactome:R-HSA-2247514 | MARK AS OVER ANNOTATED | Summary: Reactome models exogenous HSPH1 as a SCARF1 ligand that is endocytosed, which places it in the endocytic vesicle lumen. Reason: This location applies only to extracellular HSPH1 taken up as a scavenger-receptor ligand (e.g. in chaperone-antigen vaccine settings). HSPH1 has no known function in endocytic vesicles, and its native site of action is the cytosol. Supporting Evidence: Reactome:R-HSA-2247514 The SCARF1:ligand complex is endocytosed |
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Download this section (compressed HTML)Q: Which of the three human Hsp110s (HSPH1, HSPA4/Apg-2, HSPA4L/Apg-1) carries most of the Hsp70-dependent disaggregation in different cell types and under heat stress, given that immunodepletion of HSPH1 from cytosol only slightly reduced disaggregase activity whereas depletion of Apg-2 had a strong effect?
Q: Should GO gain a molecular function term for in-situ holdase activity (keeping denatured proteins soluble without folding them), now that unfolded protein binding is obsolete? Mammalian Hsp110s are a prime example.
Q: Does human HSPH1 have measurable intrinsic ATPase activity? The Hatayama group found none for Hsp105alpha/beta, while Raviol et al. reported intrinsic ATPase for human Apg-2.
Experiment: Measure nucleotide-exchange rates and Hsp70/DNAJB1-dependent disaggregation of luciferase aggregates side by side with purified HSPH1, HSPA4 and HSPA4L, and test an HSPH1 acidic-loop or NBD-interface mutant, to separate NEF potency from substrate-binding contributions.
Experiment: Use isoform-specific knockdown and rescue in human cells to compare HSPH1 alpha and the heat-specific beta isoform in recovery from heat-induced aggregation, quantified by detergent-insoluble proteome profiling.
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