hip-1 encodes the Caenorhabditis elegans ortholog of Hsp70-interacting protein (Hip/ST13), a member of the FAM10 family and a co-chaperone of the cytosolic Hsp70 (Hsc70) chaperone system. The protein has a modular architecture: an N-terminal dimerization domain (Hip_N) that drives homo-oligomerization into a tetramer, a central tetratricopeptide-repeat (TPR) region that binds the ATPase (nucleotide-binding) domain of Hsp70, and a C-terminal STI1/DP domain. Hip binds the ADP-bound state of Hsp70 and stabilizes it, slowing ADP release and prolonging the high-affinity association of Hsp70 with substrate; because Hip and nucleotide-exchange factors bind Hsp70 in a mutually exclusive manner, Hip acts as an attenuator of the Hsp70 reaction cycle that biases the system toward substrate holding and folding rather than release and degradation. Hip also has intrinsic holdase activity, binding non-native polypeptides to prevent their aggregation, but it lacks ATPase activity and cannot refold substrates on its own. In C. elegans, HIP-1 acts through Hsp70 to suppress proteotoxic aggregation in vivo, and it is predominantly cytosolic, consistent with a role in the cytosolic protein quality-control network. It is distinct from the C. elegans HOP/Stip1 ortholog sti-1, which occupies a different node of the Hsp70/Hsp90 system.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-holdase activity (GO:0140309).
Justification: hip-1: Hip, the HIP-1 ortholog, binds non-native (reduced, carboxymethylated) but not native alpha-lactalbumin, cannot refold denatured proteins, and holds clients independently of the Hsp70 ATPase cycle. Caveat: in vitro, Hip at near-stoichiometric levels inhibited refolding of alkaline phosphatase and malate dehydrogenase, which sits awkwardly with the 'folding-competent' clause of the proposed definition; release of held clients is expected to require Hsp70, so this is read as holding without release rather than as loss of folding competence, but it is noted here for GO editors. Obsolete GO:0051082 captured binding only; GO:0044183 requires assisting folding, and GO:0140309 (relabelled 'unfolded protein holdase activity') keeps a carrier-specific definition requiring escort to an acceptor molecule or location, which is not demonstrated here. See go-ontology#30552.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred biological process. HIP-1 is an Hsp70 co-chaperone that cooperates with Hsc70 in the folding of newly synthesized and non-native polypeptides; protein folding is the core process it participates in. Reason: Consistent with the conserved FAM10/Hip co-chaperone role and with experimental evidence from orthologs that Hip cooperates with Hsc70 in polypeptide folding and plays a critical role in protein folding in the eukaryotic cytoplasm. Supporting Evidence: PMID:8999928 The homo-oligomeric Hip protein cooperates with the 70-kDa heat shock cognate Hsc70 in the folding of newly synthesized polypeptide chains PMID:9183013 play a critical role in protein folding in the eukaryotic cytoplasm |
| GO:0030544 Hsp70 protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core, defining molecular function of a Hip-family co-chaperone: HIP-1 binds the N-terminal ATPase (nucleotide-binding) domain of Hsp70/Hsc70, specifically in the ADP state, and stabilizes the high substrate-affinity conformation. Reason: This is the informative, partner-specific molecular function of the protein and is supported by biochemical mapping in orthologs showing Hip binds the Hsc70 ATPase domain exclusively and by structural work showing it brackets the ATPase domain to lock in ADP. Supporting Evidence: PMID:9528774 Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70 PMID:7585962 One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules |
| GO:0005634 nucleus | IEA GO_REF:0000117 | REMOVE | Summary: Electronic (ARBA machine-learning) cellular-component annotation with no experimental support. Hip/ST13 is an established cytosolic co-chaperone of the cytosolic Hsp70 machinery, and there is no evidence for nuclear localization of C. elegans HIP-1. Reason: Over-propagated electronic inference that conflicts with the well-established cytosolic biology of Hip-family co-chaperones; not supported by any experimental or phylogenetic evidence for this gene. |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-derived (IPR034649, Hip_N) molecular function. HIP-1 genuinely homo-oligomerizes (dimer of dimers / tetramer) through its N-terminal Hip_N domain, which provides avidity for binding multiple Hsp70 molecules. Reason: Self-association is real and functionally relevant but is a structural property rather than the informative core molecular function; retained as non-core. The N-terminal oligomerization determinant and the tetrameric state are documented experimentally in orthologs. Supporting Evidence: PMID:8999928 a domain required for homo-oligomerization was identified at the extreme amino terminus of Hip PMID:9183013 the chaperone forms a tetramer similar to what has been reported for the native protein from rat liver cytosol |
| GO:0070013 intracellular organelle lumen | IEA GO_REF:0000117 | REMOVE | Summary: Electronic (ARBA machine-learning) cellular-component annotation with no experimental support and inconsistent with the cytosolic localization of Hip-family co-chaperones. Reason: Over-propagated electronic inference; an organelle-lumen location is not supported by any experimental or phylogenetic evidence for HIP-1 and conflicts with its cytosolic function. |
| GO:1902494 catalytic complex | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Electronic (ARBA machine-learning) annotation placing HIP-1 in a catalytic complex. HIP-1 itself is non-catalytic (no ATPase activity); it transiently associates with the catalytic Hsp70 ATPase, but "catalytic complex" is generic and mischaracterizes HIP-1's own role. Reason: Uninformative and potentially misleading: HIP-1 does not catalyze a reaction and is not a stable structural subunit of a defined catalytic complex; its interaction with Hsp70 is transient and regulatory. Supporting Evidence: PMID:9183013 The recombinant form of Hip did not catalyze the hydrolysis of ATP and ATP analogs |
| GO:0005783 endoplasmic reticulum | HDA PMID:21611156 Determining the sub-cellular localization of proteins within... | KEEP AS NON CORE | Summary: High-throughput direct-assay localization from a body-wall-muscle GFP-localizome: T12D8.8::GFP fell in category 6, which includes the ER/SR alongside dense bodies and the M-line/thick filaments. Reason: Experimental (HDA) but from muscle-specific overexpression of a C-terminally GFP-tagged protein, which the authors explicitly caution may perturb localization; retained as a non-core, muscle-context localization rather than the core cytosolic site of action. Supporting Evidence: PMID:21611156 They appear to be in the dense bodies, M-line and/or thick filaments, as well as the ER or SR PMID:21611156 the presence or perhaps over expression of the GFP-tagged protein may be disruptive |
| GO:0030017 sarcomere | HDA PMID:21611156 Determining the sub-cellular localization of proteins within... | KEEP AS NON CORE | Summary: High-throughput GFP-localizome placing T12D8.8::GFP at sarcomeric structures (M-line/thick filaments) in body-wall muscle (category 6). Reason: Experimental (HDA) but from muscle overexpression of a GFP fusion with acknowledged tagging/overexpression caveats; a genuine sarcomeric quality-control role is biologically plausible for a chaperone but unconfirmed for HIP-1, so kept as non-core. Supporting Evidence: PMID:21611156 They appear to be in the dense bodies, M-line and/or thick filaments, as well as the ER or SR |
| GO:0055120 striated muscle dense body | HDA PMID:21611156 Determining the sub-cellular localization of proteins within... | KEEP AS NON CORE | Summary: High-throughput GFP-localizome placing T12D8.8::GFP at the dense body (Z-disk analog) in body-wall muscle (category 6). Reason: Experimental (HDA) but from muscle overexpression of a GFP fusion with acknowledged tagging/overexpression caveats; retained as a non-core, muscle-context localization rather than the core cytosolic site of action. Supporting Evidence: PMID:21611156 They appear to be in the dense bodies, M-line and/or thick filaments, as well as the ER or SR |
| GO:0005829 cytosol | ISS PMID:9183013 Characterization of the molecular-chaperone function of the ... | NEW | Summary: Proposed core localization. Hip/ST13 orthologs are predominantly cytosolic co-chaperones of the cytosolic Hsp70 machinery, and worm HIP-1 acts through Hsp70 in the cytosol; the cytosol is inferred as the primary site of action (the muscle GFP-overexpression pattern notwithstanding). Reason: Not present in GOA but strongly supported by ortholog localization (native Hip purifies from cytosol) and by the cytosolic Hsp70-dependent proteostasis role demonstrated in the worm. Supporting Evidence: PMID:9183013 the native protein from rat liver cytosol |
| GO:1903334 positive regulation of protein folding | ISS PMID:23812373 Structure and function of Hip, an attenuator of the Hsp70 ch... | NEW | Summary: Proposed biological process. By stabilizing the ADP-bound state and attenuating the Hsp70 cycle, HIP-1 biases the chaperone system toward productive substrate holding and folding and enhances aggregation prevention by Hsp70. Reason: Not present in GOA but follows directly from the attenuator mechanism and the in vivo anti-aggregation phenotype; captures the regulatory direction of HIP-1's effect on folding. Supporting Evidence: PMID:23812373 This mechanism explains how Hip enhances aggregation prevention by Hsp70 |
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Download this section (compressed HTML)Q: Which endogenous C. elegans proteins are obligate HIP-1 clients, and does HIP-1 loss produce a phenotype (development, lifespan, proteotoxic-stress resistance, muscle maintenance) under normal conditions?
Q: Does endogenous HIP-1 localize to the cytosol in most tissues, and is the muscle sarcomeric/ER pattern seen on overexpression a genuine site of function?
Experiment: Generate a hip-1 loss-of-function allele (deletion or auxin-inducible degron) and phenotype development, brood size, lifespan, thermotolerance, and heat/proteotoxic stress resistance, with and without sti-1/HOP and hsp-90 co-depletion to test redundancy in the chaperone network.
Hypothesis: HIP-1 buffers proteotoxic stress by stabilizing Hsp70-substrate complexes on endogenous clients.
Type: genetics / phenotyping
Experiment: Immunoprecipitate CRISPR-tagged endogenous HIP-1 (and its Hsp70 partner HSP-1) from staged worms and identify co-purifying substrates by mass spectrometry, comparing basal and heat-stressed conditions.
Hypothesis: HIP-1 has a defined set of endogenous folding clients in the worm.
Type: interaction proteomics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous physiological clients/substrates of C. elegans HIP-1, and the loss-of-function phenotype of hip-1 under normal (non-transgenic) conditions, are undefined. The only direct in vivo worm evidence uses an overexpressed heterologous aggregation reporter (human alpha-synuclein), so it does not reveal which native worm proteins depend on HIP-1 or what its loss does to development, lifespan, or stress resistance.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: The conserved molecular mechanism is solid (HIP-1 binds the Hsp70 ADP state, attenuates the chaperone cycle, and has holdase activity) and genetic epistasis in the worm shows HIP-1 acts through Hsp70. What is unknown is the native client set and the organismal phenotype of HIP-1 loss.
Significance: Without native clients or a described phenotype, HIP-1's dedicated biological role in the worm cannot be separated from redundant, buffered co-chaperone functions (the sti-1/HOP and Hsp90 arms), leaving its importance for proteostasis in the intact animal unquantified.
What would resolve it: Phenotype a hip-1 deletion/RNAi allele across development, lifespan, and proteotoxic-stress paradigms, and identify endogenous clients by immunoprecipitation-mass spectrometry of tagged endogenous HIP-1.
Provenance (the field's own admissions):
Gap: Where endogenous HIP-1 acts in the C. elegans cell is not directly measured. Cytosolic localization is inferred from mammalian orthologs, and the only worm localization data come from muscle-specific GFP overexpression that placed the protein at dense bodies, the M-line/thick filaments, and the ER/SR; whether HIP-1 has a genuine sarcomeric/muscle quality-control role is unconfirmed.
OPEN BIOLOGY CC_DARK
What is known: Mammalian Hip/ST13 is firmly cytosolic. The worm GFP-overexpression screen reported a muscle sarcomeric/ER pattern for T12D8.8, but with explicit tagging/overexpression caveats and no endogenous-localization confirmation.
Significance: Distinguishing a general cytosolic role from a dedicated sarcomeric/muscle quality-control function would clarify whether HIP-1 contributes to muscle protein maintenance, a tissue where chaperone machinery is known to service the contractile apparatus.
What would resolve it: CRISPR endogenous tagging of hip-1 followed by in vivo imaging across tissues, and tissue-specific rescue/depletion to test a muscle-autonomous requirement.
Provenance (the field's own admissions):
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