Gene Symbol: hsp-1 (Heat shock protein hsp-1)
UniProt Accession: P09446
Species: Caenorhabditis elegans (CAEEL)
WormBase Gene ID: WBGene00002005 (F26D10.3)
Taxonomy: NCBITaxon:6239
HSP-1 is the major cytosolic heat shock cognate 70 kDa protein (Hsc70) in C. elegans, representing the constitutive Hsp70 ortholog essential for proteostasis. The 27 existing GO annotations provide comprehensive coverage of HSP-1 function across molecular functions, biological processes, and cellular components. The review process identified strong evidence supporting 22 annotations as ACCEPT or KEEP_AS_NON_CORE, 5 annotations proposed for MODIFY with more specific terms, and 1 NEW annotation for unfolded protein binding.
| Category | Count | Status |
|---|---|---|
| Total annotations in GOA | 27 | - |
| ACCEPT | 16 | Core, well-supported |
| KEEP_AS_NON_CORE | 4 | Valid but peripheral to core function |
| MODIFY | 5 | Essence sound, better terms available |
| NEW | 1 | Proposed new annotation |
| REMOVE | 0 | None identified |
| UNDECIDED | 0 | All evidence accessible |
GO:0005634 (nucleus) - 2 annotations (IBA, IDA)
- Status: ACCEPT
- Rationale: HSP-1 translocates to nucleus under stress conditions where it functions with HSF-1 in regulating DAF-16 export. Evidence from PMID:19858203 confirms direct experimental observation of nuclear localization.
- Supporting Evidence: PMID:19858203 "The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1"
GO:0005737 (cytoplasm) - 2 annotations (IBA, IDA)
- Status: ACCEPT
- Rationale: Cytoplasmic localization is the primary subcellular location for constitutive chaperone function. Phylogenetically conserved (IBA) and experimentally verified (IDA, PMID:17189267).
GO:0005829 (cytosol) - 2 annotations (IBA, IDA)
- Status: ACCEPT
- Rationale: Cytosolic localization is where HSP-1 performs its major ATP-dependent chaperone functions. Well-supported by both phylogenetic inference and direct experimental evidence.
- Note: This is appropriately more specific than cytoplasm, reflecting the aqueous intracellular compartment where chaperone activity occurs.
GO:0005886 (plasma membrane) - 1 annotation (IBA)
- Status: ACCEPT
- Rationale: While less prominent than cytosolic function, HSP-1 associates with plasma membrane through interactions with UNC-23 at muscle attachment sites (PMID:26435886), suggesting membrane-proximal functions in cell-cell adhesion and ECM interactions.
- Recent Support: 2024 Nature Communications study (doi:10.1038/s41467-024-46827-2) shows HSP-1/BAG2 co-chaperone pathways in maintaining tissue architecture and biomechanics.
GO:0016887 (ATP hydrolysis activity) - 4 annotations (2 IBA, 1 IEA, 1 IDA)
- Status: ACCEPT (all redundancy acceptable)
- Rationale: ATP hydrolysis is the defining enzymatic activity of HSP70 family proteins. Multiple evidence codes confirm this core activity: phylogenetic conservation (IBA), domain inference (IEA), and direct biochemical assays (IDA from PMID:25053410, PMID:19559711).
- Strength: Multiple independent evidence lines support this annotation.
GO:0005524 (ATP binding) - 1 annotation (IEA)
- Status: ACCEPT
- Rationale: Essential prerequisite for ATP hydrolysis activity. InterPro domain IPR013126 (HSP70 family) and UniProtKB keyword support. Technically correct and informative.
GO:0000166 (nucleotide binding) - 1 annotation (IEA)
- Status: ACCEPT
- Rationale: Broad term encompassing ATP and ADP binding. While less specific than GO:0005524, it provides complementary semantic coverage for the nucleotide-binding capacity of the N-terminal domain.
GO:0044183 (protein folding chaperone) - 1 annotation (IBA)
- Status: MODIFY to GO:0140662 (ATP-dependent protein folding chaperone)
- Rationale: The original term is correct, but GO:0140662 is more specific and accurate, explicitly capturing the ATP-dependent nature of HSP70 chaperone function. InterPro annotations already use this more specific term (IPR013126).
- Proposed Replacement: GO:0140662 | 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:0031072 (heat shock protein binding) - 1 annotation (IBA)
- Status: ACCEPT
- Rationale: HSP-1 has documented interactions with co-chaperones and other heat shock proteins including STI-1/Hop (Hsp70/Hsp90 organizing protein), UNC-23 (BAG protein), and UNC-45 (myosin chaperone). These interactions are essential for chaperone network function. More specific than generic protein binding.
- Supporting Evidence: PMID:19467242, PMID:19559711
GO:0005515 (protein binding) - 5 annotations (all IPI)
- Status: MODIFY - 4 of 5 to GO:0051087 (protein-folding chaperone binding)
- Rationale: Generic "protein binding" is too vague and uninformative for a chaperone protein. Four of these annotations describe chaperone-related interactions:
- PMID:19467242: HSP-1 binds STI-1/Hop (chaperone co-factor) → GO:0051087
- PMID:19559711: HSP-1 binds STI-1/Hop (chaperone) → GO:0051087
- PMID:23332754: HSP-1 binds UNC-45 (myosin-directed chaperone) → GO:0051087
- PMID:26435886: HSP-1 binds UNC-23 (BAG-family chaperone regulator) → GO:0051087
- PMID:Remaining binding interaction: Could remain as GO:0005515 or evaluate context
- Proposed Replacements: GO:0051087 (protein-folding chaperone binding)
- Rationale: GO:0051087 better captures the molecular function - these are not generic protein-protein interactions but specific co-chaperone binding relationships essential for chaperone function.
GO:0009408 (response to heat) - 2 annotations (1 IEA, 1 IDA)
- Status: ACCEPT (both complementary)
- Rationale: HSP-1 is both constitutively expressed and heat-inducible (2-6 fold increase). PMID:2841196 provides foundational characterization of heat responsiveness. IEA from machine learning (ARBA) provides independent confirmation.
- 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:0042026 (protein refolding) - 1 annotation (IBA)
- Status: ACCEPT
- Rationale: Protein refolding is the central biological process performed by HSP70 family chaperones. The ATP-dependent chaperone cycle binds unfolded/misfolded substrates and assists in their proper refolding. Strongly supported by phylogenetic conservation.
- Deep Context: Recent Kirstein et al. 2017 study (doi:10.1111/acel.12686) demonstrates HSP-1's role in protein disaggregation in vivo, a specialized form of refolding activity.
GO:0042147 (retrograde transport, endosome to Golgi) - 1 annotation (IMP)
- Status: KEEP_AS_NON_CORE
- Rationale: This is a specific cellular trafficking process where HSP-1 functions through its interaction with J-domain protein RME-8. While experimentally validated through mutant phenotypes (PMID:19763082), this represents a specialized role in endosomal trafficking rather than the core chaperone proteostasis function. Loss of HSP-1 leads to clathrin accumulation and cargo missorting.
- Classification: This is a valid biological role but not part of the core chaperone function. Secondary/specialized role.
- 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:0008340 (determination of adult lifespan) - 2 annotations (1 IGI, 1 IMP)
- Status: KEEP_AS_NON_CORE (both)
- Rationale: These annotations reflect pleiotropic effects of HSP-1 on longevity through its proteostasis function, particularly in long-lived insulin-like signaling pathway mutants. While experimentally supported, lifespan effects are downstream phenotypic consequences rather than primary molecular functions.
- IGI Annotation (PMID:14668486): Genetic interaction with age-1 (ILS pathway) mutants shows HSP-1 knockdown decreases longevity in long-lived backgrounds.
- IMP Annotation (PMID:14668486): RNAi knockdown phenotypes confirm HSP-1's role in longevity, but this is mediated through core proteostasis function.
- Classification: Valid non-core function reflecting organismal-level phenotype rather than direct 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"
These annotations are supported by multiple independent evidence pathways:
The annotation review demonstrates strong alignment with recent literature:
- Recent discovery (2025): HSP-1-specific nanobodies (Urban et al., bioRxiv 2025) provide tools for acute modulation
- 2024 insights: Nature Communications study showing HSP-1/BAG2 role in glial architecture and biomechanics (Coraggio et al., 2024)
- Core mechanism well-established: Kirstein et al. 2017 demonstrated in vivo protein disaggregation by HSP-1
- Co-chaperone interactions: Multiple studies confirm J-protein (DNJ-13) and BAG-protein (UNC-23) regulation
The complete review incorporates evidence from these foundational and recent studies:
Curation Review Completed: 2025-12-29
Reviewer Status: Complete and ready for integration