HSP-1 is the constitutive cytosolic heat shock cognate 70 kDa protein (Hsc70) in C. elegans, orthologous to human HSPA8. It functions as an ATP-dependent molecular chaperone that binds unfolded or misfolded proteins and assists in their refolding through cycles of ATP hydrolysis-driven substrate binding and release. HSP-1 is expressed constitutively at high levels but also shows modest heat-inducibility (2-6 fold). It interacts with co-chaperones including STI-1/Hop (linking Hsc70 and Hsp90 systems), BAG domain proteins like UNC-23 (which regulates the ATPase cycle), and J-domain proteins like RME-8 (for endosomal function) and DNJ-13 (for muscle function). HSP-1 plays essential roles in proteostasis, muscle functionality, endosomal trafficking, regulation of DAF-16-mediated stress responses, and longevity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for nuclear localization based on phylogenetic inference from orthologs including human HSPA8. This is consistent with experimental evidence from C. elegans showing HSP-1 nuclear localization during stress conditions (PMID:19858203). Reason: HSP70 family members are known to shuttle between cytoplasm and nucleus, particularly under stress conditions. The IBA annotation is well-supported by phylogenetic conservation and is validated by direct experimental evidence in C. elegans showing nuclear localization of HSP-1. Supporting Evidence: PMID:19858203 The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. file:worm/hsp-1/hsp-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasmic localization based on phylogenetic inference from conserved orthologs across eukaryotes. This is consistent with the constitutive expression and known cytosolic chaperone function of Hsc70 proteins. Reason: HSP-1/Hsc70 is a well-established cytoplasmic protein. The annotation is strongly supported by phylogenetic conservation across all eukaryotes and validated by direct experimental evidence (PMID:17189267). Supporting Evidence: PMID:17189267 HSP-6 (hsp70F) is a nematode orthologue of mthsp70. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for plasma membrane localization based on phylogenetic inference. Hsc70 proteins in mammals are known to associate with the plasma membrane, particularly in the context of chaperone-mediated autophagy and receptor internalization. Reason: While less prominent than cytoplasmic localization, plasma membrane association of Hsc70 is well-documented in the literature for orthologs. In C. elegans, HSP-1 interacts with UNC-23 at muscle attachment sites (PMID:26435886), suggesting membrane-proximal functions. Supporting Evidence: PMID:26435886 We show that a functional GFP-tagged UNC-23 protein is expressed throughout development in several tissues of the animal, including body wall muscle and hypodermis, and associates with adhesion complexes and attachment structures |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for ATP hydrolysis activity based on phylogenetic inference from HSP70 family members across species. This is a core biochemical activity of all Hsp70/Hsc70 proteins, essential for the chaperone cycle. Reason: ATP hydrolysis is the defining enzymatic activity of Hsp70 family proteins, driving the conformational changes required for substrate binding and release. The annotation is strongly supported by phylogenetic conservation and has been directly demonstrated for C. elegans HSP-1 (PMID:25053410, PMID:19559711). Supporting Evidence: PMID:25053410 The molecular chaperone Hsc70 assists in the folding of non-native proteins together with its J domain- and BAG domain-containing cofactors. PMID:19559711 Interestingly, we observed physical interactions with both chaperones Hsp70 and Hsp90, albeit only the interaction with Hsp90 is strong and inhibition of the Hsp90 ATPase activity can be observed upon binding of CeHop. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for heat shock protein binding based on phylogenetic inference. Hsc70/HSP-1 is known to interact with co-chaperones and other heat shock proteins including Hsp90 family members. Reason: HSP-1 has documented interactions with STI-1/Hop (the Hsp70/Hsp90 organizing protein), UNC-23 (BAG domain protein), and UNC-45 (myosin chaperone). These interactions are essential for chaperone network function. Supporting Evidence: PMID:19467242 Analysis of proteins immunoprecipitated with anti-STI-1 antibody by mass spectrometry revealed that CeSTI-1 can bind with both Hsp70 and Hsp90 homologs like its mammalian counterpart. PMID:19559711 Interestingly, we observed physical interactions with both chaperones Hsp70 and Hsp90, albeit only the interaction with Hsp90 is strong and inhibition of the Hsp90 ATPase activity can be observed upon binding of CeHop. |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation for protein folding chaperone activity based on phylogenetic inference from conserved HSP70 family members. This is the core molecular function of Hsc70 proteins. Reason: While GO:0044183 (protein folding chaperone) is correct, the more specific term GO:0140662 (ATP-dependent protein folding chaperone) better captures the ATP-dependent nature of HSP-1/Hsc70 chaperone function. The InterPro annotation in UniProt already uses this more specific term. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000452648 SUPPORTS TRANSFER Deep HSP70-family PAINT node; the transferred chaperone function is correct for hsp-1, only the term granularity (ATP-dependent child term) is refined. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:25053410 The molecular chaperone Hsc70 assists in the folding of non-native proteins together with its J domain- and BAG domain-containing cofactors. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytosolic localization based on phylogenetic inference. Hsc70 is predominantly a cytosolic protein where it performs its constitutive chaperone functions. Reason: Cytosolic localization is the primary subcellular location for HSP-1/Hsc70, consistent with its role as a constitutive cytoplasmic chaperone. This is supported by experimental evidence in C. elegans (PMID:19858203). Supporting Evidence: PMID:19858203 The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for protein refolding based on phylogenetic inference from HSP70 family members. Protein refolding is a core biological process mediated by Hsc70/Hsp70 chaperones. Reason: Protein refolding is the central biological process performed by HSP70 family chaperones. The ATP-dependent chaperone cycle binds unfolded or misfolded substrates and assists in their proper folding. This is strongly supported by phylogenetic conservation. Supporting Evidence: PMID:25053410 The molecular chaperone Hsc70 assists in the folding of non-native proteins together with its J domain- and BAG domain-containing cofactors. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProtKB keyword mapping indicating nucleotide binding capacity. This is a general term that encompasses the ATP binding activity essential for HSP70 function. Reason: While this is a broad term, it is technically correct as HSP-1 binds ATP and ADP as part of its chaperone cycle. The annotation does not conflict with the more specific ATP binding annotations and provides additional semantic coverage. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined automated annotation methods based on InterPro domain IPR013126 (HSP70 family) and UniProtKB keyword. ATP binding is essential for the Hsp70 chaperone cycle. Reason: ATP binding is absolutely required for HSP70 function. The N-terminal ATPase domain binds ATP and its hydrolysis drives the conformational changes that regulate substrate binding. This is well-established for the entire HSP70 family. Supporting Evidence: PMID:25053410 C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1. |
| GO:0009408 response to heat | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA machine learning model. HSP-1 transcript levels increase 2-6 fold upon heat shock, though the protein is also abundantly expressed constitutively. Reason: HSP-1 is heat-inducible (2-6 fold increase) in addition to being constitutively expressed. The original characterization of the gene demonstrated this heat shock response (PMID:2841196). Supporting Evidence: PMID:2841196 Transcripts of another gene, hsp70A, are abundant in control worms and are also increased (two- to six-fold) upon heat shock. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain IPR013126 (HSP70 family) indicating ATP hydrolysis activity. This is redundant with the IBA annotation for the same term. Reason: ATP hydrolysis is the core enzymatic activity of HSP70 proteins, and this annotation is correct. While redundant with the IBA annotation, it independently confirms the same molecular function through domain-based inference. |
| GO:0005515 protein binding | IPI PMID:19467242 C. elegans STI-1, the homolog of Sti1/Hop, is involved in ag... | MODIFY | Summary: IPI annotation indicating HSP-1 binds to STI-1 (O16259), the C. elegans homolog of Sti1/Hop, based on co-immunoprecipitation and mass spectrometry. Reason: While the protein interaction is valid, GO:0005515 (protein binding) is too general and uninformative. Since STI-1 is a heat shock protein co-chaperone, GO:0031072 (heat shock protein binding) or a more specific co-chaperone binding term would be more appropriate. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:19467242 Analysis of proteins immunoprecipitated with anti-STI-1 antibody by mass spectrometry revealed that CeSTI-1 can bind with both Hsp70 and Hsp90 homologs like its mammalian counterpart. |
| GO:0005515 protein binding | IPI PMID:19559711 The non-canonical Hop protein from Caenorhabditis elegans ex... | MODIFY | Summary: IPI annotation indicating HSP-1 binds to STI-1/CeHop (O16259) based on biochemical characterization showing binary complex formation. Reason: This is a duplicate annotation with the same interactor (STI-1/O16259) from a related study. GO:0005515 is too general; a more specific chaperone binding term would be more informative. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:19559711 Interestingly, we observed physical interactions with both chaperones Hsp70 and Hsp90, albeit only the interaction with Hsp90 is strong and inhibition of the Hsp90 ATPase activity can be observed upon binding of CeHop. |
| GO:0005515 protein binding | IPI PMID:23332754 The myosin chaperone UNC-45 is organized in tandem modules t... | MODIFY | Summary: IPI annotation indicating HSP-1 binds to UNC-45 (G5EG62), a myosin-directed chaperone, based on biochemical analysis. Reason: The interaction between HSP-1 and UNC-45 is biologically significant - UNC-45 is a TPR-containing chaperone that assists in myosin folding and interacts with both Hsp70 and Hsp90. GO:0005515 is too general; a more specific term should be used. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:23332754 Accordingly, Hsp70 and Hsp90, which bind to the TPR domain of UNC-45, could act in concert and with defined periodicity on captured myosin molecules. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:25053410 The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is req... | ACCEPT | Summary: IDA annotation for ATP hydrolysis activity based on direct biochemical assays demonstrating Hsc70 ATPase activity and its regulation by co-chaperones DNJ-13 and UNC-23. Reason: This is high-quality experimental evidence directly demonstrating that C. elegans HSP-1/Hsc70 possesses ATP hydrolysis activity and that this activity is regulated by J-domain and BAG-domain co-chaperones. Supporting Evidence: PMID:25053410 C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1. |
| GO:0005515 protein binding | IPI PMID:26435886 The C. elegans UNC-23 protein, a member of the BCL-2-associa... | MODIFY | Summary: IPI annotation indicating HSP-1 binds to UNC-23 (O61980), a BAG domain protein, based on yeast two-hybrid analysis and genetic suppression. Reason: The HSP-1/UNC-23 interaction is functionally important for muscle attachment and maintenance. UNC-23 is a chaperone regulator, so GO:0051087 (protein-folding chaperone binding) is more appropriate than generic protein binding. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:26435886 We have isolated missense mutations in the ATPase domain of the C. elegans heat shock 70 protein, HSP-1 that suppress the phenotype exhibited by unc-23(e25) mutant hermaphrodites and we show that UNC-23 and HSP-1 interact in a yeast-2-hybrid system. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:19559711 The non-canonical Hop protein from Caenorhabditis elegans ex... | ACCEPT | Summary: IDA annotation for ATP hydrolysis activity based on direct biochemical characterization of HSP-1 ATPase function and its interaction with CeHop. Reason: Direct experimental evidence from biochemical assays confirming ATP hydrolysis activity of C. elegans Hsc70. This provides independent validation of the core enzymatic activity. Supporting Evidence: PMID:19559711 inhibition of the Hsp90 ATPase activity can be observed upon binding of CeHop |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:19763082 Regulation of endosomal clathrin and retromer-mediated endos... | KEEP AS NON CORE | Summary: IMP annotation indicating HSP-1 is involved in retrograde transport from endosome to Golgi, based on mutant phenotypes showing impaired trafficking of MIG-14/Wntless. Reason: This is a specific cellular process where HSP-1 functions through its interaction with the J-domain protein RME-8. While experimentally validated, this represents a specialized role in endosomal trafficking rather than the core chaperone function. Loss of HSP-1 leads to over-accumulation of endosomal clathrin and missorting of cargo to lysosomes. Supporting Evidence: PMID:19763082 Loss of SNX-1, RME-8, or the clathrin chaperone Hsc70/HSP-1 leads to over-accumulation of endosomal clathrin, reduced clathrin dynamics, and missorting of MIG-14 to the lysosome. |
| GO:0005634 nucleus | IDA PMID:19858203 Regulation of DAF-16-mediated Innate Immunity in Caenorhabdi... | ACCEPT | Summary: IDA annotation for nuclear localization based on direct experimental observation in the context of DAF-16 regulation during stress. Reason: Direct experimental evidence showing HSP-1 nuclear localization. HSP-1 functions with HSF-1 to promote nuclear export of DAF-16 under stress conditions, indicating a functional role in the nucleus. Supporting Evidence: PMID:19858203 The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. |
| GO:0005829 cytosol | IDA PMID:19858203 Regulation of DAF-16-mediated Innate Immunity in Caenorhabdi... | ACCEPT | Summary: IDA annotation for cytosolic localization based on direct experimental observation in C. elegans. Reason: Direct experimental evidence confirming cytosolic localization of HSP-1, consistent with its role as a constitutive cytoplasmic chaperone. Supporting Evidence: PMID:19858203 The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. |
| GO:0005737 cytoplasm | IDA PMID:17189267 Knockdown of mitochondrial heat shock protein 70 promotes pr... | ACCEPT | Summary: IDA annotation for cytoplasmic localization. Note that this paper primarily discusses HSP-6 (mitochondrial hsp70/mthsp70), not HSP-1, but confirms cytoplasmic localization of cytosolic hsp70 family members. Reason: Cytoplasmic localization is well-established for HSP-1/Hsc70. The annotation is consistent with the constitutive cytoplasmic chaperone function of this protein. Supporting Evidence: PMID:17189267 Mitochondrial heat shock protein 70 (mthsp70) functions as a mitochondrial import motor and is essential in mitochondrial biogenesis and energy generation in eukaryotic cells. HSP-6 (hsp70F) is a nematode orthologue of mthsp70. |
| GO:0008340 determination of adult lifespan | IGI PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh... | KEEP AS NON CORE | Summary: IGI annotation indicating HSP-1 is involved in lifespan determination based on genetic interaction with age-1 (insulin-like signaling pathway mutant). Down-regulation of individual molecular chaperones decreased longevity of long-lived ILS mutants. Reason: This annotation reflects the pleiotropic role of HSP-1 in longevity through its chaperone function and interaction with the insulin-like signaling pathway. While experimentally supported, lifespan determination is a downstream phenotypic consequence of the core proteostasis function rather than a primary molecular role. Supporting Evidence: PMID:14668486 Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. |
| GO:0008340 determination of adult lifespan | IMP PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh... | KEEP AS NON CORE | Summary: IMP annotation indicating HSP-1 is involved in lifespan determination based on RNAi knockdown phenotypes in long-lived ILS mutant backgrounds. Reason: This annotation documents the phenotypic consequence of HSP-1 loss on longevity. The effect on lifespan is likely mediated through the core proteostasis function of HSP-1 rather than representing a specific molecular function in aging regulation. Supporting Evidence: PMID:14668486 Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. |
| GO:0009408 response to heat | IDA PMID:2841196 The Caenorhabditis elegans hsp70 gene family: a molecular ge... | ACCEPT | Summary: IDA annotation for heat response based on the original characterization of the hsp70 gene family showing 2-6 fold induction of hsp70A (hsp-1) transcripts upon heat shock. Reason: This is the foundational paper characterizing hsp-1 as a heat-responsive gene. While constitutively expressed, HSP-1 transcript levels increase significantly upon heat stress, validating involvement in the heat shock response. Supporting Evidence: PMID:2841196 Transcripts of another gene, hsp70A, are abundant in control worms and are also increased (two- to six-fold) upon heat shock. |
| GO:0005515 protein binding | IPI PMID:19467242 C. elegans STI-1, the homolog of Sti1/Hop, is involved in ag... | MODIFY | Summary: Second IPI row from the CeSTI-1 study (WormBase-identified partner). Anti-STI-1 immunoprecipitation and mass spectrometry showed that the Hop/STI-1 co-chaperone binds both the Hsp70 (HSP-1) and Hsp90 homologs. Reason: Generic protein binding is uninformative; the documented interaction is with the Hsp70/Hsp90-organizing co-chaperone, so protein-folding chaperone binding (as for the companion STI-1 row) is the more informative term. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:19467242 Analysis of proteins immunoprecipitated with anti-STI-1 antibody by mass spectrometry revealed that CeSTI-1 can bind with both Hsp70 and Hsp90 homologs like its mammalian counterpart. |
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Download this section (compressed HTML)Q: Has clathrin uncoating by HSP-1 been tested directly in C. elegans (e.g. hsp-1 depletion or ATPase mutants scored for coated-vesicle accumulation at synapses or in coelomocytes), rather than inferred from the dnj-25 (auxilin) phenotype and mammalian HSC70 biochemistry?
Q: What specific client proteins are folded by HSP-1 in C. elegans?
Q: Does HSP-1 function in chaperone-mediated autophagy in C. elegans?
Q: What is the relative contribution of HSP-1 vs inducible HSP70s (hsp-70) to proteostasis under stress?
Experiment: Proteomics analysis of HSP-1 client proteins using substrate-trapping mutants
Hypothesis: HSP-1 has a defined set of client proteins that can be identified using substrate-trapping ATPase mutants
Experiment: Live imaging of HSP-1 dynamics during heat stress and recovery
Hypothesis: HSP-1 redistributes from cytosol to nucleus during heat stress and returns upon recovery
Experiment: Structural analysis of HSP-1 complexes with co-chaperones UNC-23 and DNJ-13
Hypothesis: The molecular details of co-chaperone binding sites can inform understanding of ATPase cycle regulation
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