HSP-70 (C12C8.1) is a strictly stress-inducible cytosolic member of the HSP70 chaperone family, the C. elegans counterpart of the mammalian inducible HSPA1A/HSPA1B proteins. It is essentially undetectable under normal growth conditions and is induced more than a thousand-fold by heat shock in an HSF-1-dependent manner, which has made its promoter the standard heat-shock reporter in the worm. Like other HSP70s it has an N-terminal nucleotide-binding ATPase domain, a substrate-binding domain and a C-terminal EEVD motif for co-chaperone docking, and it functions as an ATP-dependent folding chaperone that binds exposed hydrophobic segments of denatured proteins and, with J-domain and nucleotide-exchange co-chaperones, refolds them during recovery from proteotoxic stress. Its expression is also increased by ER stress in an xbp-1-dependent manner, and HSF-1 target chaperones including the inducible HSP70s contribute to the extended lifespan of insulin-signalling mutants.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (IPR013126, Hsp_70_fam) mapping to ATP binding. HSP-70 (C12C8.1) contains the conserved HSP70 N-terminal nucleotide-binding domain. Reason: ATP binding by the NBD is intrinsic to every HSP70 and drives the chaperone cycle; the InterPro mapping is correct for this canonical, full-length cytosolic HSP70. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for nuclear activity of cytosolic HSP70s (node PTN002500132), with HSP-1 among the descendant evidence. Reason: Inducible and cognate cytosolic HSP70s shuttle into the nucleus during and after heat shock in many eukaryotes; the target lies within the cytosolic HSP70 clade that the node covers and there is no evidence of divergence. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for cytoplasm, from a deep HSP70 node (PTN002321897). Reason: HSP-70 (C12C8.1) lacks a signal peptide and mitochondrial presequence and ends in the cytosolic HSP70 EEVD motif; it is one of the four cytosolic HSP70s of C. elegans. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000117 | REMOVE | Summary: ARBA machine-learning prediction of endoplasmic reticulum lumen. Reason: HSP-70 (C12C8.1) has no N-terminal signal peptide and no KDEL/HDEL retrieval signal; it ends in the cytosolic EEVD motif. The ER-lumenal HSP70s of C. elegans are the BiP orthologues HSP-3 and HSP-4. The ARBA rule appears to have been triggered by generic HSP70 family membership and mislocalizes this cytosolic paralogue. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for cytosol (node PTN002500132) including HSP-1 as descendant evidence. Reason: HSP-70 (C12C8.1) is a cytosolic HSP70 (no targeting signal, C-terminal EEVD); cytosol is the principal site of its chaperone activity. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0005832 chaperonin-containing T-complex | IDA PMID:9434769 Subunit characterization of the Caenorhabditis elegans chape... | MARK AS OVER ANNOTATED | Summary: Leroux & Candido purified C. elegans CCT and characterized its subunits; the annotation asserts that C12C8.1 is part of the chaperonin-containing T-complex. The cached record is abstract-only; the abstract reports seven CCT subunit species of 52-65 kDa and a co-purifying HSP60, and does not mention an HSP70. Reason: CCT is a hetero-oligomeric ring of eight TCP-1-family subunits; an HSP70 is not a CCT subunit. If C12C8.1 was detected in the CCT preparation in the full text (not available to us), that reflects co-purification or a transient chaperone hand-off rather than complex membership, which is what part_of asserts. Not removed because the full text could not be read, but this is not a location or complex that describes HSP-70 function. Supporting Evidence: PMID:9434769 was purified and shown to contain at least seven subunit species ranging from 52-65 kDa PMID:9434769 Surprisingly, the co-purified HSP60 chaperonin present in the C. elegans CCT preparation has the greatest binding activity for denatured actin. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of the broad term response to stress. Reason: Correct but very general; HSP-70 (C12C8.1) is a stress-inducible HSP70 and the more specific response to heat is captured elsewhere. Acceptable as a high-level electronic annotation. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0008340 determination of adult lifespan | IGI PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh... | KEEP AS NON CORE | Summary: Morley & Morimoto showed that RNAi of individual HSF-1 target chaperones reduced the extended lifespan of insulin-like signalling mutants, but not wild-type lifespan. Reason: A genetic requirement for the extended longevity of long-lived mutants is a downstream organismal phenotype of a stress-inducible chaperone, not its core activity. Accepted as non-core in line with the treatment of the same kind of annotation on HSP-1. 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. PMID:14668486 However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. |
| GO:0009408 response to heat | IEP PMID:15280428 Compartment-specific perturbation of protein handling activa... | ACCEPT | Summary: Expression-based annotation; in this study of the mitochondrial UPR, heat shock was used as a comparison stress that induced the cytosolic heat-shock reporter but not hsp-6 or hsp-60. The cached record is abstract-only. Reason: Strong heat inducibility of C12C8.1 is extremely well documented (it is the standard phsp-70 heat-shock reporter promoter). Response to heat is a core process for this strictly inducible HSP70. Supporting Evidence: PMID:15280428 as neither heat-shock nor endoplasmic reticulum stress nor manipulations that impair mitochondrial steps in intermediary metabolism or ATP synthesis activated the mitochondrial chaperone genes PMID:23637632 Expression of this reporter is not detected under ambient growth conditions of development and adulthood (Figure 1A) and is induced strongly by HS (Figure 1B). |
| GO:0009408 response to heat | IEP PMID:28198373 Hormetic heat stress and HSF-1 induce autophagy to improve s... | ACCEPT | Summary: Kumsta et al. report >1000-fold induction of hsp-70 (C12C8.1) mRNA after hormetic heat shock. Reason: Direct expression evidence for the defining property of this gene: it is essentially silent under ambient conditions and massively induced by heat in an HSF-1-dependent manner. Supporting Evidence: PMID:28198373 As expected, this treatment markedly increased (>1000-fold) expression of the HSP genes hsp-70 (C12C8.1) and hsp-16.1. PMID:27688402 The expression of classical heat-shock genes hsp-16.41 and hsp-70 (C12C8.1) was severely compromised (>99% reduced) in hsf-1(ok600) animals exposed to heat shock compared with N2 animals |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for ATP hydrolysis activity from the HSP70 family node PTN000452648. Reason: The intrinsic ATPase of the HSP70 NBD is conserved across the family (DnaK, Ssa, HSPA1A/HSPA8, HSP-1) and is essential to the substrate-binding cycle. All catalytic residues of the NBD are conserved in this canonical HSP70. Supporting Evidence: PMID:41387410 Of the seven canonical HSP70 family chaperones found in C. elegans, four are cytosolic (HSP-1, C12C8.1, F44E5.4, F44E5.5) |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to ATP hydrolysis activity, consistent with the IBA. Reason: Redundant with the IBA; correct for a canonical HSP70. |
| GO:0030968 endoplasmic reticulum unfolded protein response | HEP PMID:12186849 A survival pathway for Caenorhabditis elegans with a blocked... | KEEP AS NON CORE | Summary: Microarray study: C12C8.1 is among the genes induced by tunicamycin in an xbp-1-dependent manner (Table I, about 2-fold log2 induction in N2). Reason: The expression evidence is real, but HSP-70 is a cytosolic chaperone and its induction during ER stress is a secondary output; it does not act in the ER lumen. Retained as a non-core response annotation. Supporting Evidence: PMID:12186849 Of these 34 genes, 26 were uninduced or induced to significantly lower levels (P < 0.05) in the xbp-1 mutant strain. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for heat shock protein binding (node PTN000452648); HSP70s bind J-domain proteins (HSP40s), nucleotide exchange factors and, via the EEVD tail, TPR co-chaperones such as Hop/STI-1 and CHIP. Reason: Binding of HSP40/J-domain co-chaperones and TPR co-chaperones via the C-terminal EEVD motif, which HSP-70 (C12C8.1) retains, is a conserved property of cytosolic HSP70s and is how the chaperone cycle is regulated. Consistent with the treatment of the same IBA on HSP-1. |
| GO:0036498 IRE1-mediated unfolded protein response | HEP PMID:12186849 A survival pathway for Caenorhabditis elegans with a blocked... | KEEP AS NON CORE | Summary: Same microarray result as the ER UPR row: tunicamycin induction of C12C8.1 is attenuated in xbp-1 mutants. Reason: xbp-1 dependence of the induction supports placing the expression response downstream of IRE-1/XBP-1 signalling, but HSP-70 is an output gene of that response rather than a component of the signalling pathway. Non-core. Supporting Evidence: PMID:12186849 Of these 34 genes, 26 were uninduced or induced to significantly lower levels (P < 0.05) in the xbp-1 mutant strain. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for protein refolding (node PTN000452648). Reason: ATP-dependent refolding of heat-denatured proteins is the canonical function of stress-inducible HSP70s and is the process the inducible HSP70s execute during recovery from heat shock. Consistent with HSP-1. |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA for protein folding chaperone (node PTN000452648). Reason: Correct in essence, but HSP70 folding activity is ATP-dependent; the more specific child GO:0140662 ATP-dependent protein folding chaperone describes it precisely. Same treatment as the corresponding IBA on HSP-1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000452648 · HSP70 family node SUPPORTS TRANSFER Folding-chaperone activity is well grounded across the HSP70 seeds (DnaK, HSPA1A/B, HSPA8); the transfer is sound and only the granularity is refined to the ATP-dependent child term. Proposed replacements: ATP-dependent protein folding chaperone |
| GO:0044183 protein folding chaperone | ISS GO_REF:0000024 | MODIFY | Summary: Curator ISS transfer of protein folding chaperone activity from human HSPA1A (P0DMV8), the inducible HSP70. Reason: HSP-70 is the worm counterpart of the human inducible HSP70s (HSPA1A/B) and the transfer is sound; refine to the ATP-dependent child term, as for the IBA. Proposed replacements: ATP-dependent protein folding chaperone |
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Download this section (compressed HTML)Q: Which client proteins does inducible HSP-70 refold after heat shock that the constitutive HSC70 HSP-1 cannot handle?
Q: Are HSP-70 (C12C8.1) and F44E5.4/F44E5.5 functionally redundant, given their near-identical sequences and shared induction pattern?
Experiment: Generate a C12C8.1 deletion (and C12C8.1; F44E5.4/5 compound mutant) and measure thermotolerance, recovery of heat-denatured luciferase reporters and aggregation of metastable proteins after heat shock.
Hypothesis: Inducible HSP70s are required for refolding of heat-denatured proteins and for acquired thermotolerance, with partial redundancy among C12C8.1 and F44E5.4/5.
hsp-70 encodes a heat-shock protein that is a member of the hsp70 family of molecular chaperones.
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