hsp-110 (ORF C30C11.4) encodes the C. elegans member of the HSP110/HSPH subfamily of the Hsp70 chaperone superfamily, orthologous to yeast Sse1/Sse2 and human HSPH1/HSPA4/ HSPA4L (apg-1). Like other HSP110 proteins it is a cytosolic, ATP-binding relative of Hsp70 that acts as a nucleotide-exchange factor (NEF) for canonical Hsp70 chaperones: its ATP-loaded nucleotide-binding domain, together with a three-helix-bundle domain, clamps the Hsp70 nucleotide-binding domain and drives ADP release, resetting the Hsp70 ATPase/folding cycle. Unlike canonical Hsp70s, HSP110 does not depend on its own ATP hydrolysis for this activity and can additionally bind non-native polypeptides directly (holdase activity). In C. elegans, HSP-110 operates within the cytosolic chaperone and disaggregation network together with Hsp70 and Hsp40/DnaJ partners to limit the accumulation of misfolded, aggregation-prone proteins; loss of HSP-110 increases aggregation of a misfolding-prone protein in neurons. As an HSF-1-regulated heat-shock protein it also contributes to stress resistance and to the extended lifespan of insulin/IGF-1-signaling mutants.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0000774
adenyl-nucleotide exchange factor activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Core molecular function. HSP-110 is the C. elegans HSP110-family nucleotide-exchange factor for Hsp70. This IBA is well grounded: the phylogenetic reference set includes yeast Sse1/Sse2 and human HSPH1, for which NEF activity is directly established.
Reason: HSP110 proteins are the principal cytosolic NEFs for Hsp70; the ATP-loaded HSP110 NBD engages the Hsp70 NBD and drives ADP release. This is the defining, informative molecular function of the gene and should be retained as core.
Supporting Evidence:
PMID:16688211
acts as an efficient nucleotide exchange factor (NEF) for both yeast cytosolic Hsp70s, Ssa1p and Ssb1p. The mechanism involves formation of a stable nucleotide-sensitive complex, but does not require ATP hydrolysis by Sse1p
PMID:18555782
the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70. Mutations that abolish NEF activity are lethal, thus defining nucleotide exchange on Hsp70 as an essential function of Sse1p
|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetically propagated nuclear localization. HSP110-family proteins are primarily cytosolic; some mammalian HSPH1 can partition to the nucleus, but there is no direct C. elegans evidence for a nuclear pool of HSP-110.
Reason: Retain as a possible minor/shuttling location inherited from the family tree, but it is not the site of the core function; the cytosol is where HSP-110 acts on Hsp70.
|
|
GO:0006457
protein folding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: HSP-110 participates in the cytosolic protein-folding process as the Hsp70 NEF; its NEF activity stimulates Hsp70-mediated refolding of denatured substrates.
Reason: Valid and central biological process for an Hsp70 co-chaperone/NEF; consistent with the experimental IMP protein-folding annotation from the worm and with the conserved family mechanism.
Supporting Evidence:
PMID:16688211
The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of thermally denatured luciferase
|
|
GO:0005829
cytosol
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Core location. HSP110 proteins are cytosolic Hsp70 relatives, and the worm HSP-110 acts on cytosolic Hsp70.
Reason: The cytosol is the compartment where HSP-110 performs its NEF function; well supported at the family level and consistent with worm proteostasis assays in cytoplasm.
Supporting Evidence:
PMID:16688211
The Hsp110 proteins, exclusively found in the eukaryotic cytosol
|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: HSP-110 retains the Hsp70-family nucleotide-binding domain and binds ATP; ATP loading of its NBD is functionally required for NEF activity (the ATP-bound NBD clamps the Hsp70 NBD to release ADP).
Reason: ATP/adenyl-nucleotide binding is genuine and mechanistically essential for HSP-110 NEF function, not a spurious fold-based call.
Supporting Evidence:
PMID:18555782
the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70
|
|
GO:0006950
response to stress
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Generic stress-response term from ARBA. HSP-110 is a heat-shock protein and HSF-1 transcriptional target, so involvement in the stress response is correct but uninformatively broad relative to the specific proteostasis roles captured elsewhere.
Reason: True but too general; the specific and better-supported terms (response to topologically incorrect protein, protein folding) convey the actual role. Keep as a broad, non-core annotation.
|
|
GO:0016887
ATP hydrolysis activity
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: Propagated from the generic Hsp70 ATPase fold. HSP110-family proteins have only weak, atypical ATPase activity, and their defining NEF mechanism explicitly does NOT require ATP hydrolysis by HSP110; HSP110 also does not use the canonical Hsp70 nucleotide-driven allosteric cycle.
Reason: The term is not categorically impossible (HSP110 binds and may slowly turn over ATP), but attributing a functional ATP hydrolysis activity over-states the biochemistry: it is an electronic call from the shared Hsp70 domain, whereas the characterized HSP110 role is NEF and holdase, with ATP binding (not hydrolysis) being the load-bearing property. Flag as likely over-annotation rather than remove outright.
Supporting Evidence:
PMID:16688211
The mechanism involves formation of a stable nucleotide-sensitive complex, but does not require ATP hydrolysis by Sse1p
PMID:18555782
does not employ the nucleotide-dependent allostery and peptide-binding mode of canonical Hsp70s
|
|
GO:0006457
protein folding
|
IMP
PMID:22242008 A genetic screening strategy identifies novel regulators of ... |
ACCEPT |
Summary: Experimental WormBase annotation. In a genome-wide RNAi screen, C30C11.4 (hsp-110) was one of six chaperone-class genes among the polyglutamine (Q35/Q37) aggregation modifiers (a Class A strong modifier), linking it to the muscle-cell protein-folding environment.
Reason: Experimental (IMP) annotation supported by the screen; consistent with HSP-110's role as an Hsp70 NEF in cytosolic protein folding. Deferred to the WormBase curator who assessed the full dataset.
Supporting Evidence:
PMID:22242008
F08H9.3; cyn-11; cyn-12; C30C11.4; dnj-22; phb-2
|
|
GO:0035966
response to topologically incorrect protein
|
IMP
PMID:19165329 An ALS-linked mutant SOD1 produces a locomotor defect associ... |
ACCEPT |
Summary: Experimental WormBase annotation and a core biological role. RNAi and the gk533 loss-of-function allele of hsp-110/C30C11.4 strongly increase aggregation of neuronally expressed misfolding-prone mutant human SOD1(G85R); HSP-110 acts here with an Hsp70 (stc-1) and a DnaJ (dnj-19), i.e. the metazoan Hsp70-Hsp40-Hsp110 anti-aggregation machinery.
Reason: Directly supported experimental annotation for this gene; captures HSP-110's in vivo function in handling misfolded (topologically incorrect) proteins.
Supporting Evidence:
PMID:19165329
including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron specific Hsp16 (F08H9.4)
PMID:19165329
Three of these were validated as strongly increasing aggregation when mutant alleles were crossed with G85R-YFP
|
|
GO:0008340
determination of adult lifespan
|
IGI
PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh... |
KEEP AS NON CORE |
Summary: Experimental IGI annotation. HSF-1-target molecular chaperones, when down-regulated, shorten the extended lifespan of long-lived insulin/IGF-1-signaling mutants; the WormBase annotation records a genetic interaction of hsp-110 with age-1 (WBGene00000090). This is a pleiotropic, downstream organismal consequence of HSP-110's chaperone activity rather than its core molecular function.
Reason: Retain as a genuine experimental (genetic-interaction) annotation - do not remove - but classify as non-core: lifespan determination reflects HSP-110's contribution to the proteostasis/stress network, not a distinct molecular activity. Cached reference is abstract-only; deferred to the WormBase curator who read the full text.
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:0051082
unfolded protein binding
|
ISS
PMID:18555782 Structural basis for the cooperation of Hsp70 and Hsp110 cha... |
NEW |
Summary: Proposed molecular function not currently in GOA. In addition to nucleotide exchange, HSP110-family proteins bind non-native polypeptides directly (holdase activity), and in the worm HSP-110 loss increases aggregation of misfolding-prone SOD1 in neurons - consistent with a substrate-binding contribution to keeping clients soluble for Hsp70.
Reason: Captures HSP-110's substrate-binding/holdase arm, complementing its NEF activity; more informative than a generic protein-binding term and grounded in the family structure plus the in vivo anti-aggregation phenotype.
Supporting Evidence:
PMID:18555782
direct interactions of substrate with Sse1p may support Hsp70-assisted protein folding in a cooperative process
|
Q: Which C. elegans Hsp70 (HSP-1, STC-1, or HSP-70) and which J-domain/Hsp40 proteins form the physiological HSP-110-dependent disaggregation machine in each tissue?
Suggested experts: C. elegans proteostasis biologists, Hsp70/Hsp110 chaperone biochemists
Q: Is HSP-110 required to dissolve pre-formed aggregates, or only to prevent their formation, in worm neurons and muscle?
Suggested experts: Protein-aggregation/disaggregase biologists
Experiment: Affinity-purify endogenously tagged HSP-110 from C. elegans lysate and identify Hsp70, Hsp40/J-protein, and client partners to define the worm disaggregation network and native substrates.
Type: Affinity purification / mass spectrometry
Experiment: Engineer NEF-dead, ATPase-dead, and substrate-binding-dead hsp-110 alleles and test each for rescue of aggregation/disaggregation and lifespan phenotypes to dissect which molecular property (nucleotide exchange, ATP hydrolysis, holdase) is required in vivo.
Type: Separation-of-function genetics
Experiment: Reconstitute disaggregation of aggregated model substrates with purified worm HSP-110, Hsp70, and Hsp40 to test whether HSP-110 is required and rate-limiting for the reaction.
Type: In vitro disaggregation reconstitution
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether C. elegans HSP-110 is genetically and biochemically required for Hsp70/Hsp40-mediated protein DISAGGREGATION in vivo, and the identity of its physiological worm Hsp70 (HSP-1 vs STC-1 vs HSP-70) and J-protein/Hsp40 partners in that reaction, are undetermined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: It is established that HSP-110 is an HSP110-family Hsp70 NEF (conserved from yeast Sse1 to human HSPH1) and that in neurons its loss (RNAi and the gk533 allele) increases aggregation of misfolding-prone SOD1 alongside an Hsp70 (stc-1) and a DnaJ (dnj-19). What is NOT established for the worm is a reconstituted or genetically defined Hsp70-Hsp40-Hsp110 disaggregase, its obligate partner set, and whether HSP-110 is required for active dissolution of pre-formed aggregates (as opposed to preventing their formation).
Significance: Metazoan protein disaggregation depends on a cooperative Hsp70-Hsp40-Hsp110 system. Defining the worm partners and the requirement for HSP-110 would connect its molecular NEF activity to organismal proteostasis and neuroprotection, and clarify which chaperone axis to target in C. elegans neurodegeneration models.
What would resolve it: Tissue-specific hsp-110 loss-of-function combined with aggregation/disaggregation reporters and photoconvertible aggregation-clearance assays; affinity-purification/mass-spectrometry of tagged HSP-110 from worm lysate to define Hsp70/J-protein partners; in vitro reconstitution of a worm disaggregase.
Provenance (the field's own admissions):
Gap: The endogenous C. elegans client repertoire of HSP-110 is undefined: which native metastable proteins depend on HSP-110 NEF/holdase activity, and in which tissues, is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: HSP-110 demonstrably modifies aggregation of heterologous, aggregation-prone reporters (polyglutamine and mutant human SOD1) and, at the family level, HSP110 NEF activity stimulates Hsp70-mediated refolding of denatured model substrates such as luciferase. No endogenous physiological worm client of HSP-110 has been mapped.
Significance: Client identity determines where HSP-110 activity is rate-limiting for proteostasis and which phenotypes (muscle, neuron, germline, aging) are mechanistically downstream of the NEF function.
What would resolve it: Chaperone-client capture (e.g. interactomics of tagged HSP-110, or aggregate proteomics in hsp-110 loss-of-function) to enumerate native substrates.
Provenance (the field's own admissions):
Gap: Whether HSP-110's own weak/atypical ATPase activity, and any Hsp70-independent holdase function, have a physiological role in C. elegans is untested.
OPEN BIOLOGY MF_DARK
What is known: The defining HSP110 NEF mechanism requires ATP BINDING but not ATP hydrolysis by HSP110, and HSP110 does not use the canonical Hsp70 nucleotide-driven allosteric peptide-binding cycle; direct substrate binding by Hsp110 has been observed in vitro. The in vivo relevance of HSP-110 ATP hydrolysis and of a standalone holdase mode in the worm has not been probed.
Significance: Resolving this would settle whether the IEA-propagated ATP hydrolysis activity is functionally meaningful for HSP-110 or a fold-based over-annotation, and whether HSP-110 contributes to proteostasis independently of Hsp70.
What would resolve it: Structure-guided separation-of-function alleles (NEF-dead vs ATPase-dead vs substrate-binding-dead) tested for rescue of hsp-110 proteostasis phenotypes in vivo, plus in vitro ATPase and holdase assays on purified worm HSP-110.
Provenance (the field's own admissions):
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The C. elegans gene hsp-110 (systematic name C30C11.4; UniProt accession Q05036) encodes Heat Shock Protein 110, a member of the HSP70 superfamily belonging to the HSP110/Grp170 subfamily. The C. elegans genome encodes three Hsp70-related putative nucleotide exchange factors (NEFs): two ER-localized Grp170 family members and a single cytosolic HSP110 member, which is C30C11.4/HSP-110 (rampelt2012metazoanhsp70machines pages 8-9, tittelmeier2020thehsp110hsp70disaggregation pages 2-4). This makes HSP-110 the sole cytosolic HSP110-type NEF in the nematode, underscoring its non-redundant importance in cytoplasmic protein quality control.
HSP-110 shares the core domain organization of canonical Hsp70 proteins but with distinguishing features. It contains an N-terminal nucleotide-binding domain (NBD), a β-sandwich peptide-binding domain (PBD-β), and an α-helical bundle domain (PBD-α), along with longer insertions and C-terminal extensions relative to canonical Hsp70 (bracher2015thenucleotideexchange pages 2-4). A particularly notable structural feature is a negatively charged ~100-residue acidic insertion loop located between strands 7 and 8 of the β-sandwich subdomain, which is unique to the HSP110 family (sousa2014structuralmechanismsof pages 3-4). Additionally, the interdomain linker between the NBD and the substrate-binding domain is charged rather than hydrophobic, further distinguishing HSP-110 from canonical Hsp70 proteins (yakubu2018rolesofthe pages 1-3).
The primary biochemical function of HSP-110 is to serve as a nucleotide exchange factor (NEF) for Hsp70/Hsc70 chaperones. HSP-110 catalyzes the release of ADP from Hsp70, allowing ATP to rebind and thereby triggering substrate release from the Hsp70 peptide-binding cleft (sousa2014structuralmechanismsof pages 3-4, rampelt2012metazoanhsp70machines pages 1-2). This NEF activity is the most potent among eukaryotic cytosolic Hsp70 NEFs, making HSP110 proteins the dominant regulators of the Hsp70 chaperone cycle in the cytosol (sousa2014structuralmechanismsof pages 3-4).
Structural studies of the yeast ortholog Sse1 (in complex with Ssa1/Hsp70) have revealed the molecular mechanism of HSP110-mediated nucleotide exchange. The NBDs of HSP110 and Hsp70 face each other asymmetrically, forming extensive contacts between opposite NBD lobes (andreasson2008insightsintothe pages 1-2). A critical second contact involves the protruding C-terminal β-helical subdomain of HSP110 interacting with the periphery of Hsp70 NBD lobe II. The α-helix bundle domain of HSP110 fixes the Hsp70 NBD in an open conformation through highly conserved contacts (bracher2015thenucleotideexchange pages 2-4). This causes lobe displacement or rotation in the Hsp70 NBD, reducing Hsp70's affinity for ADP and enabling nucleotide exchange (yakubu2018rolesofthe pages 3-4). Importantly, ATP binding to the HSP110 NBD is required for complex formation with Hsp70, but ATP hydrolysis by HSP110 is not essential for its NEF function—ATPase-deficient HSP110 mutants can still rescue lethality from HSP110 deletion (yakubu2018rolesofthe pages 1-3, bracher2015thenucleotideexchange pages 2-4).
Beyond its NEF function, HSP-110 also acts as a passive chaperone ("holdase") capable of recognizing and binding unfolded or partially folded polypeptides to prevent their aggregation, without requiring energy input (yakubu2018rolesofthe pages 3-4). HSP110 displays faster binding kinetics and a preference for aromatic residue-rich peptides, in contrast to Hsp70's preference for aliphatic sequences (sousa2014structuralmechanismsof pages 3-4). However, in the context of protein disaggregation, the holdase function of HSP110 appears dispensable—studies using yeast Hsp110 mutants with partially inactivated substrate-binding domains showed no detrimental effect on disaggregation activity (yakubu2018rolesofthe pages 4-6).
HSP-110's most critical physiological role is as an essential component of the metazoan Hsp70-based protein disaggregation machinery. Unlike bacteria, fungi, and plants, which employ dedicated AAA+ ATPase Hsp100/Hsp104 disaggregases, metazoan organisms (including C. elegans) lack cytosolic Hsp100 homologs and instead rely on a tripartite chaperone system comprising Hsp70 (HSC70), J-domain proteins (Hsp40s), and HSP110 to solubilize protein aggregates (rampelt2012metazoanhsp70machines pages 1-2).
The disaggregation cycle operates as follows:
Aggregate recognition and Hsp70 recruitment: J-domain proteins (JDPs) of class A and class B recognize and target aggregated protein substrates, recruiting Hsp70 to the aggregate surface (nillegoda2015metazoanhsp70basedprotein pages 2-4, kirstein2017invivoproperties pages 1-1).
Hsp70 activation: JDPs stimulate Hsp70 ATPase activity, locking Hsp70 in its ADP-bound, high-affinity substrate-binding state on the aggregate.
HSP110-mediated nucleotide exchange: HSP110 is recruited to Hsp70 at the aggregate surface and catalyzes ADP-to-ATP exchange, which triggers substrate release and resets Hsp70 for another binding cycle (sztangierska2024earlystepsof pages 1-2).
Aggregate remodeling: Repeated cycles of Hsp70 binding and release, powered by HSP110-mediated nucleotide exchange, generate mechanical forces that extract polypeptides from aggregates. This may operate through an entropic pulling mechanism, where the bulky HSP110–Hsp70 complex transiently increases the effective volume near the aggregate, amplifying the unfolding/pulling forces (rebeaud2025ishsp110boosting pages 1-4).
Substrate refolding or degradation: Released polypeptides are either refolded by the Hsp70 system or handed off to degradation pathways.
Recent work (2024) has demonstrated that HSP110 plays a major role at the initial stages of disaggregation, catalyzing the recruitment of thick Hsp70 assemblies onto aggregate surfaces, which converts large aggregates into smaller species more readily processed by chaperones (sztangierska2024earlystepsof pages 1-2). HSP110's stimulation of Hsp70 is substantially stronger when working with class B J-domain proteins compared to class A, and this interaction requires the Hsp70 EEVD motif. Notably, HSP110 can also disrupt JDP-Hsp70 interactions, which may improve disaggregation efficiency but can inhibit activity if HSP110 concentrations exceed optimal sub-stoichiometric levels (sztangierska2024earlystepsof pages 1-2). This finding highlights that balanced interplay between the co-chaperones and Hsp70 is critical for effective disaggregation.
HSP-110 is identified as the sole cytosolic HSP110-type nucleotide exchange factor in C. elegans (tittelmeier2020thehsp110hsp70disaggregation pages 2-4). Its primary site of function is the cytoplasm, where it supports the Hsp70-based disaggregation machinery. Studies in yeast have demonstrated that the orthologous Hsp110 proteins (Sse1/Sse2) function in both the cytosol and nucleus, and that tethering Hsp110 away from either compartment impairs disaggregation in that location (kaimal2017coordinatedhsp110and pages 15-18). By analogy, C. elegans HSP-110 likely operates in both the cytoplasm and nucleus, though direct nuclear localization data in the worm are limited. The ER-localized Grp170 family members serve as the HSP70 NEFs in the endoplasmic reticulum, functionally complementing HSP-110 in that compartment (rampelt2012metazoanhsp70machines pages 8-9).
Complete hsp-110 knockout is lethal in C. elegans, demonstrating its essential role in normal cellular function (tittelmeier2020thehsp110hsp70disaggregation pages 2-4). Systemic RNAi knockdown also affects growth, development, and fertility (tittelmeier2020thehsp110hsp70disaggregation pages 2-4).
The landmark study by Rampelt et al. (2012) provided direct in vivo evidence for HSP-110's role in protein disaggregation using transgenic C. elegans expressing luciferase-YFP in muscle cells as an aggregation sensor. After heat shock (1 hour at 35°C), luciferase-YFP formed aggregated foci. In control animals, these aggregates were completely resolved within 24 hours of recovery at 20°C. However, in animals where hsp-110 was knocked down by RNAi, the aggregated luciferase foci persisted and remained insoluble and immobile at both 12 and 24 hours post-heat shock (rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 8-9). Critically, knockdown of the alternative NEF bag-1 did not impair aggregate solubilization, demonstrating the non-redundant, specialized role of HSP-110 in the disaggregation machinery (rampelt2012metazoanhsp70machines pages 10-11, rampelt2012metazoanhsp70machines pages 9-10).
Under normal growth conditions at 20°C, hsp-110 RNAi causes only a modest lifespan reduction of 1–2 days. However, following heat shock, hsp-110-depleted animals exhibit a dramatic lifespan reduction of approximately 4.5 days compared to controls (rampelt2012metazoanhsp70machines pages 9-10). This indicates that HSP-110 becomes especially critical under conditions of high protein aggregation load, consistent with its role in the disaggregation pathway (rampelt2012metazoanhsp70machines pages 9-10).
A pivotal study by Tittelmeier et al. (2020) revealed that the HSP-110/HSP70 disaggregation system is a "double-edged sword" in the context of amyloid disease models. While HSP-110 depletion impaired general proteostasis (preventing resolubilization of amorphous aggregates and compromising cellular folding capacity), it paradoxically reduced α-synuclein foci formation, cell-to-cell transmission, and toxicity in C. elegans disease models (tittelmeier2020thehsp110hsp70disaggregation pages 1-2, tittelmeier2020thehsp110hsp70disaggregation pages 4-5). Specifically:
These findings demonstrate that the HSP70 disaggregation activity, while essential for maintaining cellular proteostasis, is also involved in generating toxic, spreading-competent amyloid species through fibril fragmentation, which can seed further polymerization and prion-like propagation (tittelmeier2020thehsp110hsp70disaggregation pages 6-9, tittelmeier2020thehsp110hsp70disaggregation pages 2-4).
HSP-110 knockdown shows complex age-dependent phenotypes. In young animals, HSP-110 depletion provides some tolerance to α-synuclein and polyQ toxicity. However, during aging, HSP-110-depleted animals show accelerated decline in motility compared to controls, likely due to progressive proteostasis collapse (tittelmeier2020thehsp110hsp70disaggregation pages 6-9). Age-dependent protein aggregation (measured by FlucSM foci) forms more rapidly in HSP-110 knockdown backgrounds, and the protective effects observed in younger animals are lost with age (tittelmeier2020thehsp110hsp70disaggregation pages 6-9).
In vivo studies in C. elegans have revealed that HSP-110 functions within a broader cooperative J-protein network. Class A and class B J-proteins (JDPs) form a flexible interactive network that relocalizes to protein aggregates upon heat shock and preferentially recruits constitutive Hsc70 for disaggregation (kirstein2017invivoproperties pages 1-1). This cooperation between J-protein classes is required for organismal health, promoting thermotolerance, maintenance of fecundity, and extended viability after heat stress (kirstein2017invivoproperties pages 7-8). Disruption of these cooperative interactions exacerbates age-dependent aggregation of polyQ proteins (kirstein2017invivoproperties pages 7-8).
HSP-110 represents a distinct evolutionary branch of the Hsp70 superfamily that has acquired specialized NEF function. In metazoan lineages that lost cytosolic Hsp100/Hsp104 disaggregases, the Hsp70-JDP-Hsp110 system became the primary disaggregation machinery (rampelt2012metazoanhsp70machines pages 1-2). This evolutionary transition underscores the importance of HSP-110 as a critical adaptation enabling metazoan cells to maintain proteostasis without dedicated AAA+ disaggregases. The system achieves disaggregation through a fundamentally different mechanism—iterative Hsp70 cycling powered by HSP110 NEF activity—rather than the threading mechanism employed by Hsp104 ring hexamers (torrente2013themetazoanprotein pages 4-5).
The following table provides a comprehensive overview of the key functional attributes of C. elegans hsp-110:
| Feature | Detail | Key Reference |
|---|---|---|
| Gene identity | hsp-110 corresponds to C30C11.4 in Caenorhabditis elegans and encodes the organism’s single cytosolic HSP110-type nucleotide exchange factor (NEF) for HSP70; this matches the UniProt entry Q05036 and distinguishes it from two ER-localized Grp170 family members. | (rampelt2012metazoanhsp70machines pages 8-9, tittelmeier2020thehsp110hsp70disaggregation pages 2-4) |
| Protein family | HSP-110 belongs to the HSP70 superfamily / HSP110 subfamily. Like other HSP110 proteins, it contains an N-terminal nucleotide-binding domain, β-sandwich peptide-binding domain, and α-helical bundle, with characteristic insertions including an acidic loop that distinguishes HSP110 proteins from canonical HSP70s. | (yakubu2018rolesofthe pages 1-3, bracher2015thenucleotideexchange pages 2-4, sousa2014structuralmechanismsof pages 3-4, yakubu2018rolesofthe pages 11-12) |
| Primary molecular function | The best-supported primary function is to act as a nucleotide exchange factor for HSP70/HSC70, promoting ADP release and ATP rebinding on HSP70 and thereby enabling substrate release and repeated chaperone cycles during protein quality control. In metazoan disaggregation, this NEF activity is the key catalytic contribution of HSP110. | (sousa2014structuralmechanismsof pages 3-4, yakubu2018rolesofthe pages 1-3, yakubu2018rolesofthe pages 3-4, rampelt2012metazoanhsp70machines pages 1-2) |
| Biochemical role in disaggregation | HSP-110 is essential for the HSP70-HSP40-HSP110 disaggregase system that solubilizes and reactivates aggregated proteins after stress. Direct work in C. elegans showed that HSP-110 is required for clearing heat-induced luciferase aggregates in vivo. | (rampelt2012metazoanhsp70machines pages 10-11, rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 8-9) |
| ATP dependence / mechanism | Structural and biochemical studies of the HSP110 family show that ATP binding to HSP110 is required for productive interaction with HSP70, whereas ATP hydrolysis by HSP110 is not essential for its NEF function. HSP110 opens the HSP70 NBD through extensive NBD-NBD contacts and associated conformational changes. | (yakubu2018rolesofthe pages 1-3, bracher2015thenucleotideexchange pages 2-4, andreasson2008insightsintothe pages 1-2) |
| Additional chaperone properties | Beyond NEF activity, HSP110 family proteins can function as holdase chaperones that bind unfolded proteins and help prevent aggregation, though in disaggregation assays the central requirement is still the HSP70-directed NEF activity. | (yakubu2018rolesofthe pages 3-4, sousa2014structuralmechanismsof pages 3-4, yakubu2018rolesofthe pages 4-6) |
| Subcellular localization | In C. elegans, HSP-110 is identified as the sole cytosolic HSP110-type NEF. Available direct evidence supports cytosolic function, especially in muscle-cell proteostasis assays; by analogy with other eukaryotic HSP110 systems, related proteins can support disaggregation in both cytosol and nucleus, but C. elegans-specific nuclear localization evidence is limited. | (tittelmeier2020thehsp110hsp70disaggregation pages 2-4, kaimal2017coordinatedhsp110and pages 15-18) |
| Key interacting partners | Core functional partners are HSP70/HSC70 and J-domain proteins (HSP40s). The disaggregation machinery depends on cooperation between HSP110 and HSP70, while class A and class B J-proteins target aggregates and help recruit/activate HSP70 for extraction and refolding cycles. | (kirstein2017invivoproperties pages 1-1, rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 1-2, nillegoda2015metazoanhsp70basedprotein pages 2-4, sztangierska2024earlystepsof pages 1-2) |
| Pathway involvement | hsp-110 functions in the cytosolic proteostasis network, specifically the metazoan HSP70-based protein disaggregation pathway that responds to heat stress, age-associated aggregation, and misfolded proteins. It is part of stress-recovery and aggregate-clearance pathways rather than a classic signaling enzyme pathway. | (kirstein2017invivoproperties pages 1-1, rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 1-2) |
| Relationship to heat stress | In worms subjected to heat shock, HSP-110 is required for efficient recovery from proteotoxic stress. Loss of HSP-110 leaves heat-induced aggregates persistent and insoluble, indicating failure of post-stress protein recovery. | (rampelt2012metazoanhsp70machines pages 1-2, rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 8-9) |
| Loss-of-function phenotype: viability | Complete hsp-110 knockout is lethal, indicating an essential housekeeping role in proteostasis. More moderate systemic RNAi knockdown also affects growth, development, and fertility. | (tittelmeier2020thehsp110hsp70disaggregation pages 2-4) |
| Loss-of-function phenotype: aggregate clearance | RNAi depletion of hsp-110 causes a strong defect in resolubilization of heat-induced luciferase aggregates in vivo; aggregates persist at 12–24 h after heat shock instead of clearing during recovery. | (rampelt2012metazoanhsp70machines pages 9-10, rampelt2012metazoanhsp70machines pages 8-9) |
| Loss-of-function phenotype: lifespan after stress | Under normal conditions, hsp-110 knockdown causes only a modest lifespan decrease, but after heat shock it causes a dramatic shortening of lifespan (~4.5 days), indicating that HSP-110 becomes especially critical under high aggregation load. | (rampelt2012metazoanhsp70machines pages 9-10) |
| Loss-of-function phenotype: amyloid models | In contrast to its protective role in general proteostasis, HSP-110 depletion can reduce α-synuclein and polyQ foci formation, spreading, and toxicity in worm disease models, showing that the disaggregase can be a double-edged sword by generating toxic amyloid-competent species while still supporting overall protein homeostasis. | (tittelmeier2020thehsp110hsp70disaggregation pages 6-9, tittelmeier2020thehsp110hsp70disaggregation pages 4-5, tittelmeier2020thehsp110hsp70disaggregation pages 1-2) |
| Expert interpretation | Authoritative reviews and mechanistic papers converge on the view that HSP110 is the major metazoan HSP70 NEF and a central amplifier of disaggregation capacity, acting early in aggregate processing and enabling efficient HSP70 cycling on difficult aggregate substrates. | (yakubu2018rolesofthe pages 4-6, nillegoda2015metazoanhsp70basedprotein pages 2-4, sztangierska2024earlystepsof pages 1-2) |
Table: This table summarizes the core functional annotation of C. elegans hsp-110/C30C11.4, including identity, molecular role, localization, partners, phenotypes, and pathway context. It is useful as a concise evidence-backed overview for gene annotation and literature review.
In conclusion, C. elegans HSP-110 (C30C11.4) is a cytosolic nucleotide exchange factor for Hsp70 that is essential for metazoan protein disaggregation. Its primary biochemical activity is catalyzing ADP release from Hsp70, enabling the iterative chaperone cycling required to extract and resolubilize aggregated proteins. HSP-110 is the sole cytosolic member of the HSP110 family in C. elegans, and its complete loss is lethal. Under proteotoxic stress conditions, HSP-110 is indispensable for aggregate clearance and organismal survival, while its activity in processing amyloid substrates represents a double-edged sword—essential for general proteostasis but also capable of generating toxic, spreading-competent amyloid species.
References
(rampelt2012metazoanhsp70machines pages 8-9): Heike Rampelt, Janine Kirstein-Miles, Nadinath B Nillegoda, Kang Chi, Sebastian R Scholz, Richard I Morimoto, and Bernd Bukau. Metazoan hsp70 machines use hsp110 to power protein disaggregation. The EMBO Journal, 31:4221-4235, Nov 2012. URL: https://doi.org/10.1038/emboj.2012.264, doi:10.1038/emboj.2012.264. This article has 383 citations.
(tittelmeier2020thehsp110hsp70disaggregation pages 2-4): Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel‐Augustin, Axel Mogk, Bernd Bukau, and Carmen Nussbaum‐Krammer. The hsp110/hsp70 disaggregation system generates spreading‐competent toxic α‐synuclein species. The EMBO Journal, May 2020. URL: https://doi.org/10.15252/embj.2019103954, doi:10.15252/embj.2019103954. This article has 119 citations.
(bracher2015thenucleotideexchange pages 2-4): Andreas Bracher and Jacob Verghese. The nucleotide exchange factors of hsp70 molecular chaperones. Frontiers in Molecular Biosciences, Apr 2015. URL: https://doi.org/10.3389/fmolb.2015.00010, doi:10.3389/fmolb.2015.00010. This article has 299 citations.
(sousa2014structuralmechanismsof pages 3-4): Rui Sousa. Structural mechanisms of chaperone mediated protein disaggregation. Frontiers in Molecular Biosciences, Sep 2014. URL: https://doi.org/10.3389/fmolb.2014.00012, doi:10.3389/fmolb.2014.00012. This article has 42 citations.
(yakubu2018rolesofthe pages 1-3): Unekwu M. Yakubu and Kevin A. Morano. Roles of the nucleotide exchange factor and chaperone hsp110 in cellular proteostasis and diseases of protein misfolding. Biological Chemistry, 399:1215-1221, Sep 2018. URL: https://doi.org/10.1515/hsz-2018-0209, doi:10.1515/hsz-2018-0209. This article has 41 citations and is from a peer-reviewed journal.
(rampelt2012metazoanhsp70machines pages 1-2): Heike Rampelt, Janine Kirstein-Miles, Nadinath B Nillegoda, Kang Chi, Sebastian R Scholz, Richard I Morimoto, and Bernd Bukau. Metazoan hsp70 machines use hsp110 to power protein disaggregation. The EMBO Journal, 31:4221-4235, Nov 2012. URL: https://doi.org/10.1038/emboj.2012.264, doi:10.1038/emboj.2012.264. This article has 383 citations.
(andreasson2008insightsintothe pages 1-2): Claes Andréasson, Jocelyne Fiaux, Heike Rampelt, Silke Druffel-Augustin, and Bernd Bukau. Insights into the structural dynamics of the hsp110–hsp70 interaction reveal the mechanism for nucleotide exchange activity. Proceedings of the National Academy of Sciences, 105:16519-16524, Oct 2008. URL: https://doi.org/10.1073/pnas.0804187105, doi:10.1073/pnas.0804187105. This article has 107 citations and is from a highest quality peer-reviewed journal.
(yakubu2018rolesofthe pages 3-4): Unekwu M. Yakubu and Kevin A. Morano. Roles of the nucleotide exchange factor and chaperone hsp110 in cellular proteostasis and diseases of protein misfolding. Biological Chemistry, 399:1215-1221, Sep 2018. URL: https://doi.org/10.1515/hsz-2018-0209, doi:10.1515/hsz-2018-0209. This article has 41 citations and is from a peer-reviewed journal.
(yakubu2018rolesofthe pages 4-6): Unekwu M. Yakubu and Kevin A. Morano. Roles of the nucleotide exchange factor and chaperone hsp110 in cellular proteostasis and diseases of protein misfolding. Biological Chemistry, 399:1215-1221, Sep 2018. URL: https://doi.org/10.1515/hsz-2018-0209, doi:10.1515/hsz-2018-0209. This article has 41 citations and is from a peer-reviewed journal.
(nillegoda2015metazoanhsp70basedprotein pages 2-4): Nadinath B. Nillegoda and Bernd Bukau. Metazoan hsp70-based protein disaggregases: emergence and mechanisms. Frontiers in Molecular Biosciences, Oct 2015. URL: https://doi.org/10.3389/fmolb.2015.00057, doi:10.3389/fmolb.2015.00057. This article has 149 citations.
(kirstein2017invivoproperties pages 1-1): Janine Kirstein, Kristin Arnsburg, Annika Scior, Anna Szlachcic, D. Lys Guilbride, Richard I. Morimoto, Bernd Bukau, and Nadinath B. Nillegoda. In vivo properties of the disaggregase function of j‐proteins and hsc70 in caenorhabditis elegans stress and aging. Aging Cell, 16:1414-1424, Oct 2017. URL: https://doi.org/10.1111/acel.12686, doi:10.1111/acel.12686. This article has 87 citations and is from a domain leading peer-reviewed journal.
(sztangierska2024earlystepsof pages 1-2): Wiktoria Sztangierska, Hubert Wyszkowski, Maria Pokornowska, Klaudia Kochanowicz, Michał Rychłowski, Krzysztof Liberek, and Agnieszka Kłosowska. Early steps of protein disaggregation by hsp70 chaperone and class b j-domain proteins are shaped by hsp110. Sep 2024. URL: https://doi.org/10.7554/elife.94795.2, doi:10.7554/elife.94795.2. This article has 24 citations.
(rebeaud2025ishsp110boosting pages 1-4): Mathieu E. Rebeaud, Bruno Fauvet, Paolo De Los Rios, and Pierre Goloubinoff. Is hsp110 boosting the basal disaggregation activity hsp70 by enhanced entropic pulling strokes? bioRxiv, Apr 2025. URL: https://doi.org/10.1101/2025.04.01.646638, doi:10.1101/2025.04.01.646638. This article has 0 citations.
(kaimal2017coordinatedhsp110and pages 15-18): Jayasankar Mohanakrishnan Kaimal, Ganapathi Kandasamy, Fabian Gasser, and Claes Andréasson. Coordinated hsp110 and hsp104 activities power protein disaggregation in saccharomyces cerevisiae. Molecular and Cellular Biology, Jun 2017. URL: https://doi.org/10.1128/mcb.00027-17, doi:10.1128/mcb.00027-17. This article has 95 citations and is from a domain leading peer-reviewed journal.
(rampelt2012metazoanhsp70machines pages 9-10): Heike Rampelt, Janine Kirstein-Miles, Nadinath B Nillegoda, Kang Chi, Sebastian R Scholz, Richard I Morimoto, and Bernd Bukau. Metazoan hsp70 machines use hsp110 to power protein disaggregation. The EMBO Journal, 31:4221-4235, Nov 2012. URL: https://doi.org/10.1038/emboj.2012.264, doi:10.1038/emboj.2012.264. This article has 383 citations.
(rampelt2012metazoanhsp70machines pages 10-11): Heike Rampelt, Janine Kirstein-Miles, Nadinath B Nillegoda, Kang Chi, Sebastian R Scholz, Richard I Morimoto, and Bernd Bukau. Metazoan hsp70 machines use hsp110 to power protein disaggregation. The EMBO Journal, 31:4221-4235, Nov 2012. URL: https://doi.org/10.1038/emboj.2012.264, doi:10.1038/emboj.2012.264. This article has 383 citations.
(tittelmeier2020thehsp110hsp70disaggregation pages 1-2): Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel‐Augustin, Axel Mogk, Bernd Bukau, and Carmen Nussbaum‐Krammer. The hsp110/hsp70 disaggregation system generates spreading‐competent toxic α‐synuclein species. The EMBO Journal, May 2020. URL: https://doi.org/10.15252/embj.2019103954, doi:10.15252/embj.2019103954. This article has 119 citations.
(tittelmeier2020thehsp110hsp70disaggregation pages 4-5): Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel‐Augustin, Axel Mogk, Bernd Bukau, and Carmen Nussbaum‐Krammer. The hsp110/hsp70 disaggregation system generates spreading‐competent toxic α‐synuclein species. The EMBO Journal, May 2020. URL: https://doi.org/10.15252/embj.2019103954, doi:10.15252/embj.2019103954. This article has 119 citations.
(tittelmeier2020thehsp110hsp70disaggregation pages 6-9): Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel‐Augustin, Axel Mogk, Bernd Bukau, and Carmen Nussbaum‐Krammer. The hsp110/hsp70 disaggregation system generates spreading‐competent toxic α‐synuclein species. The EMBO Journal, May 2020. URL: https://doi.org/10.15252/embj.2019103954, doi:10.15252/embj.2019103954. This article has 119 citations.
(kirstein2017invivoproperties pages 7-8): Janine Kirstein, Kristin Arnsburg, Annika Scior, Anna Szlachcic, D. Lys Guilbride, Richard I. Morimoto, Bernd Bukau, and Nadinath B. Nillegoda. In vivo properties of the disaggregase function of j‐proteins and hsc70 in caenorhabditis elegans stress and aging. Aging Cell, 16:1414-1424, Oct 2017. URL: https://doi.org/10.1111/acel.12686, doi:10.1111/acel.12686. This article has 87 citations and is from a domain leading peer-reviewed journal.
(torrente2013themetazoanprotein pages 4-5): Mariana P Torrente and James Shorter. The metazoan protein disaggregase and amyloid depolymerase system. Prion, 7:457-463, Nov 2013. URL: https://doi.org/10.4161/pri.27531, doi:10.4161/pri.27531. This article has 92 citations and is from a peer-reviewed journal.
(yakubu2018rolesofthe pages 11-12): Unekwu M. Yakubu and Kevin A. Morano. Roles of the nucleotide exchange factor and chaperone hsp110 in cellular proteostasis and diseases of protein misfolding. Biological Chemistry, 399:1215-1221, Sep 2018. URL: https://doi.org/10.1515/hsz-2018-0209, doi:10.1515/hsz-2018-0209. This article has 41 citations and is from a peer-reviewed journal.
Gene: hsp-110 / ORF C30C11.4 / WormBase WBGene00016250
UniProt: Q05036 (HS110_CAEEL), 776 aa, chromosome III.
Product: Heat shock protein 110 (HSP110 / HSPH-family Hsp70 relative).
ASKHA_NBD_HSP70_HSPA4_like, InterPro IPR043129) + Hsp70HSP110-family proteins are the principal cytosolic nucleotide-exchange factors (NEFs) for
Hsp70. Established biochemically/structurally in yeast (Sse1p) and conserved across
eukaryotes:
Implications for the GO annotations:
- ATP binding (GO:0005524) is genuine and functionally required: Hsp110's own NBD must be
ATP-loaded to embrace and open the Hsp70 NBD PMID:18555782.
- ATP hydrolysis (GO:0016887), in contrast, is not required for the defining NEF
activity, and Hsp110 "does not employ the nucleotide-dependent allostery and peptide-binding
mode of canonical Hsp70s" PMID:18555782.
So the IEA ATP hydrolysis activity (propagated from the generic Hsp70 fold) is an
over-annotation relative to the characterized mechanism (weak/atypical ATPase; hydrolysis
dispensable).
- Beyond NEF, Hsp110 also has intrinsic holdase / substrate-binding activity ("direct
interactions of substrate with Sse1p may support Hsp70-assisted protein folding"
PMID:18555782), and its NEF activity stimulates Hsp70-mediated refolding of denatured
substrate ("The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of
thermally denatured luciferase" PMID:16688211).
Prevents aggregation of a misfolding-prone protein in neurons in vivo (disaggregase/
holdase partner of the Hsp70 machine). In a pan-neuronal mutant human SOD1(G85R) ALS model,
an RNAi screen for modifiers of aggregation found that knockdown of a set of chaperones —
"including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron specific
Hsp16 (F08H9.4)" — strongly increased SOD1 inclusion formation PMID:19165329. The effect was confirmed with the loss-of-function allele gk533 (Table 2:
"C30C11.4 ... homolog to human apg-1 (a heat shock 110 kDa protein) 3 gk533 ++", strong
increase of inclusions). This co-set (Hsp110 + Hsp40/DnaJ + Hsp70) is exactly the metazoan
Hsp70–Hsp40–Hsp110 disaggregation machinery, giving in vivo support for
GO:0035966 (response to topologically incorrect protein). UniProt records the disruption
phenotype: "RNAi-mediated knockdown in a sod-1 mutant background results in increased
aggregation of denatured proteins in neurons" [file:worm/hsp-110/hsp-110-uniprot.txt].
Modifier of proteostasis / polyglutamine folding (protein folding, IMP). In a genome-wide
RNAi screen in body-wall muscle, C30C11.4 was one of six chaperone-class genes among the polyQ
(Q35/Q37) aggregation modifiers ("Protein Folding and transport ... Chaperone (6) F08H9.3;
cyn-11; cyn-12; C30C11.4; dnj-22; phb-2") whose knockdown suppressed polyQ aggregation
PMID:22242008. It was a Class A (strong,
Q35+Q37) modifier. This is the basis of the WormBase IMP GO:0006457 (protein folding)
annotation. (Note the direction: here knockdown suppresses aggregation, whereas in the
neuronal SOD1 model knockdown increases aggregation — i.e. the readout is model-dependent,
but both link hsp-110 to the folding/aggregation environment.)
Contributes to longevity of insulin/IGF-1-signaling (ILS) mutants (determination of adult
lifespan, IGI). Morley & Morimoto showed that "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. The WormBase IGI annotation records a genetic interaction with
WB:WBGene00000090 = age-1 (PI3K, an ILS long-lived mutant background). This paper is
abstract-only in our cache (full_text_available: false); the specific hsp-110 result is in the
full text the curator read. Treated as a real experimental annotation (do not remove); it is a
pleiotropic/downstream organismal role, not the core molecular function → KEEP_AS_NON_CORE.
nucleus (GO:0005634) is a phylogenetic propagation (mammalian HSPH1 can also behsp-110-deep-research-falcon.md, 23 citations). It independently reaches the samefile:/DOI quotes, so NONE of the falcon text is used verbatim in thesupporting_text in the review is PMID-anchored and verified against the cachedid: Q05036
gene_symbol: hsp-110
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: >-
hsp-110 (ORF C30C11.4) encodes the C. elegans member of the HSP110/HSPH subfamily of
the Hsp70 chaperone superfamily, orthologous to yeast Sse1/Sse2 and human HSPH1/HSPA4/
HSPA4L (apg-1). Like other HSP110 proteins it is a cytosolic, ATP-binding relative of
Hsp70 that acts as a nucleotide-exchange factor (NEF) for canonical Hsp70 chaperones:
its ATP-loaded nucleotide-binding domain, together with a three-helix-bundle domain,
clamps the Hsp70 nucleotide-binding domain and drives ADP release, resetting the Hsp70
ATPase/folding cycle. Unlike canonical Hsp70s, HSP110 does not depend on its own ATP
hydrolysis for this activity and can additionally bind non-native polypeptides directly
(holdase activity). In C. elegans, HSP-110 operates within the cytosolic chaperone and
disaggregation network together with Hsp70 and Hsp40/DnaJ partners to limit the
accumulation of misfolded, aggregation-prone proteins; loss of HSP-110 increases
aggregation of a misfolding-prone protein in neurons. As an HSF-1-regulated heat-shock
protein it also contributes to stress resistance and to the extended lifespan of
insulin/IGF-1-signaling mutants.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: PMID:14668486
title: Regulation of longevity in Caenorhabditis elegans by heat shock factor and
molecular chaperones.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
PubMed-verified. Abstract-only in our cache (full_text_available: false). Supports
that HSF-1-target molecular chaperones are required for the extended lifespan of
long-lived (ILS-pathway) mutants; the WormBase IGI annotation records a genetic
interaction of hsp-110 with age-1 (WBGene00000090). The gene-specific hsp-110 result
is in the full text read by the curator, not the abstract.
- id: PMID:19165329
title: An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation
and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified, full text available. Directly assays hsp-110/C30C11.4: RNAi and the
gk533 loss-of-function allele strongly increase aggregation of neuronally expressed
mutant human SOD1(G85R), placing HSP-110 with an Hsp70 (stc-1) and a DnaJ (dnj-19) in
the chaperone network that prevents misfolded-protein aggregation in vivo.
- id: PMID:22242008
title: A genetic screening strategy identifies novel regulators of the proteostasis
network.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified, full text available. C30C11.4 (hsp-110) is one of six chaperone-class
genes among the polyQ (Q35/Q37) aggregation modifiers (Class A, strong); basis of the
WormBase IMP protein-folding annotation.
- id: PMID:16688211
title: 'Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide
exchange factor.'
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified, abstract-only. Family-level (yeast Sse1p) mechanistic reference
establishing HSP110 as an Hsp70 nucleotide-exchange factor whose activity does not
require its own ATP hydrolysis; used as conserved-mechanism support for the worm
ortholog's NEF core function, not as direct worm evidence.
- id: PMID:18555782
title: Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein
folding.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified, abstract-only. Crystal structure of yeast Sse1p (Hsp110) bound to the
Hsp70 NBD; ATP-bound HSP110 NBD embraces the Hsp70 NBD to release ADP, and NEF activity
is essential. Conserved-mechanism support for the worm ortholog; also documents direct
substrate binding by Hsp110.
existing_annotations:
- term:
id: GO:0000774
label: adenyl-nucleotide exchange factor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: >-
Core molecular function. HSP-110 is the C. elegans HSP110-family nucleotide-exchange
factor for Hsp70. This IBA is well grounded: the phylogenetic reference set includes
yeast Sse1/Sse2 and human HSPH1, for which NEF activity is directly established.
action: ACCEPT
reason: >-
HSP110 proteins are the principal cytosolic NEFs for Hsp70; the ATP-loaded HSP110 NBD
engages the Hsp70 NBD and drives ADP release. This is the defining, informative
molecular function of the gene and should be retained as core.
supported_by:
- reference_id: PMID:16688211
supporting_text: >-
acts as an efficient nucleotide exchange factor (NEF) for both yeast cytosolic
Hsp70s, Ssa1p and Ssb1p. The mechanism involves formation of a stable
nucleotide-sensitive complex, but does not require ATP hydrolysis by Sse1p
- reference_id: PMID:18555782
supporting_text: >-
the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of
Hsp70, inducing opening and the release of bound ADP from Hsp70. Mutations that
abolish NEF activity are lethal, thus defining nucleotide exchange on Hsp70 as an
essential function of Sse1p
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Phylogenetically propagated nuclear localization. HSP110-family proteins are primarily
cytosolic; some mammalian HSPH1 can partition to the nucleus, but there is no direct
C. elegans evidence for a nuclear pool of HSP-110.
action: KEEP_AS_NON_CORE
reason: >-
Retain as a possible minor/shuttling location inherited from the family tree, but it is
not the site of the core function; the cytosol is where HSP-110 acts on Hsp70.
- term:
id: GO:0006457
label: protein folding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
HSP-110 participates in the cytosolic protein-folding process as the Hsp70 NEF; its NEF
activity stimulates Hsp70-mediated refolding of denatured substrates.
action: ACCEPT
reason: >-
Valid and central biological process for an Hsp70 co-chaperone/NEF; consistent with the
experimental IMP protein-folding annotation from the worm and with the conserved family
mechanism.
supported_by:
- reference_id: PMID:16688211
supporting_text: >-
The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of thermally
denatured luciferase
- term:
id: GO:0005829
label: cytosol
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Core location. HSP110 proteins are cytosolic Hsp70 relatives, and the worm HSP-110 acts
on cytosolic Hsp70.
action: ACCEPT
reason: >-
The cytosol is the compartment where HSP-110 performs its NEF function; well supported
at the family level and consistent with worm proteostasis assays in cytoplasm.
supported_by:
- reference_id: PMID:16688211
supporting_text: The Hsp110 proteins, exclusively found in the eukaryotic cytosol
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
HSP-110 retains the Hsp70-family nucleotide-binding domain and binds ATP; ATP loading of
its NBD is functionally required for NEF activity (the ATP-bound NBD clamps the Hsp70
NBD to release ADP).
action: ACCEPT
reason: >-
ATP/adenyl-nucleotide binding is genuine and mechanistically essential for HSP-110 NEF
function, not a spurious fold-based call.
supported_by:
- reference_id: PMID:18555782
supporting_text: >-
the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of
Hsp70, inducing opening and the release of bound ADP from Hsp70
- term:
id: GO:0006950
label: response to stress
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: >-
Generic stress-response term from ARBA. HSP-110 is a heat-shock protein and HSF-1
transcriptional target, so involvement in the stress response is correct but
uninformatively broad relative to the specific proteostasis roles captured elsewhere.
action: KEEP_AS_NON_CORE
reason: >-
True but too general; the specific and better-supported terms (response to
topologically incorrect protein, protein folding) convey the actual role. Keep as a
broad, non-core annotation.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
Propagated from the generic Hsp70 ATPase fold. HSP110-family proteins have only weak,
atypical ATPase activity, and their defining NEF mechanism explicitly does NOT require
ATP hydrolysis by HSP110; HSP110 also does not use the canonical Hsp70 nucleotide-driven
allosteric cycle.
action: MARK_AS_OVER_ANNOTATED
reason: >-
The term is not categorically impossible (HSP110 binds and may slowly turn over ATP),
but attributing a functional ATP hydrolysis activity over-states the biochemistry: it is
an electronic call from the shared Hsp70 domain, whereas the characterized HSP110 role is
NEF and holdase, with ATP binding (not hydrolysis) being the load-bearing property. Flag
as likely over-annotation rather than remove outright.
supported_by:
- reference_id: PMID:16688211
supporting_text: >-
The mechanism involves formation of a stable nucleotide-sensitive complex, but does
not require ATP hydrolysis by Sse1p
- reference_id: PMID:18555782
supporting_text: >-
does not employ the nucleotide-dependent allostery and peptide-binding mode of
canonical Hsp70s
- term:
id: GO:0006457
label: protein folding
evidence_type: IMP
original_reference_id: PMID:22242008
qualifier: involved_in
review:
summary: >-
Experimental WormBase annotation. In a genome-wide RNAi screen, C30C11.4 (hsp-110) was
one of six chaperone-class genes among the polyglutamine (Q35/Q37) aggregation modifiers
(a Class A strong modifier), linking it to the muscle-cell protein-folding environment.
action: ACCEPT
reason: >-
Experimental (IMP) annotation supported by the screen; consistent with HSP-110's role as
an Hsp70 NEF in cytosolic protein folding. Deferred to the WormBase curator who assessed
the full dataset.
supported_by:
- reference_id: PMID:22242008
supporting_text: 'F08H9.3; cyn-11; cyn-12; C30C11.4; dnj-22; phb-2'
- term:
id: GO:0035966
label: response to topologically incorrect protein
evidence_type: IMP
original_reference_id: PMID:19165329
qualifier: involved_in
review:
summary: >-
Experimental WormBase annotation and a core biological role. RNAi and the gk533
loss-of-function allele of hsp-110/C30C11.4 strongly increase aggregation of neuronally
expressed misfolding-prone mutant human SOD1(G85R); HSP-110 acts here with an Hsp70
(stc-1) and a DnaJ (dnj-19), i.e. the metazoan Hsp70-Hsp40-Hsp110 anti-aggregation
machinery.
action: ACCEPT
reason: >-
Directly supported experimental annotation for this gene; captures HSP-110's in vivo
function in handling misfolded (topologically incorrect) proteins.
supported_by:
- reference_id: PMID:19165329
supporting_text: >-
including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron
specific Hsp16 (F08H9.4)
- reference_id: PMID:19165329
supporting_text: >-
Three of these were validated as strongly increasing aggregation when mutant alleles
were crossed with G85R-YFP
- term:
id: GO:0008340
label: determination of adult lifespan
evidence_type: IGI
original_reference_id: PMID:14668486
qualifier: involved_in
review:
summary: >-
Experimental IGI annotation. HSF-1-target molecular chaperones, when down-regulated,
shorten the extended lifespan of long-lived insulin/IGF-1-signaling mutants; the
WormBase annotation records a genetic interaction of hsp-110 with age-1
(WBGene00000090). This is a pleiotropic, downstream organismal consequence of HSP-110's
chaperone activity rather than its core molecular function.
action: KEEP_AS_NON_CORE
reason: >-
Retain as a genuine experimental (genetic-interaction) annotation - do not remove - but
classify as non-core: lifespan determination reflects HSP-110's contribution to the
proteostasis/stress network, not a distinct molecular activity. Cached reference is
abstract-only; deferred to the WormBase curator who read the full text.
supported_by:
- reference_id: PMID:14668486
supporting_text: >-
Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1,
also decreased longevity of long-lived mutant but not wild-type animals
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: ISS
original_reference_id: PMID:18555782
qualifier: enables
review:
summary: >-
Proposed molecular function not currently in GOA. In addition to nucleotide exchange,
HSP110-family proteins bind non-native polypeptides directly (holdase activity), and in
the worm HSP-110 loss increases aggregation of misfolding-prone SOD1 in neurons -
consistent with a substrate-binding contribution to keeping clients soluble for Hsp70.
action: NEW
reason: >-
Captures HSP-110's substrate-binding/holdase arm, complementing its NEF activity; more
informative than a generic protein-binding term and grounded in the family structure plus
the in vivo anti-aggregation phenotype.
supported_by:
- reference_id: PMID:18555782
supporting_text: >-
direct interactions of substrate with Sse1p may support Hsp70-assisted protein folding
in a cooperative process
core_functions:
- description: >-
Cytosolic HSP110-family nucleotide-exchange factor (NEF) for Hsp70. The ATP-loaded HSP-110
nucleotide-binding domain, together with its three-helix-bundle domain, clamps the Hsp70
nucleotide-binding domain and triggers ADP release, resetting the Hsp70 ATPase/folding
cycle. This conserved HSP110 activity (yeast Sse1 to human HSPH1) is the defining molecular
function of HSP-110 and drives Hsp70-dependent (re)folding in the cytosol.
molecular_function:
id: GO:0000774
label: adenyl-nucleotide exchange factor activity
directly_involved_in:
- id: GO:0006457
label: protein folding
locations:
- id: GO:0005829
label: cytosol
supported_by:
- reference_id: PMID:16688211
supporting_text: >-
acts as an efficient nucleotide exchange factor (NEF) for both yeast cytosolic Hsp70s,
Ssa1p and Ssb1p. The mechanism involves formation of a stable nucleotide-sensitive
complex, but does not require ATP hydrolysis by Sse1p
- reference_id: PMID:18555782
supporting_text: >-
nucleotide exchange factors (NEFs) that remove ADP from Hsp70
- description: >-
Direct binding of non-native/unfolded polypeptides (holdase arm). Beyond nucleotide
exchange, HSP-110 can engage substrate directly, cooperating with Hsp70 to keep
aggregation-prone clients soluble; in the worm, loss of HSP-110 increases aggregation of
misfolding-prone SOD1 in neurons, consistent with a substrate-holding/anti-aggregation
contribution alongside its Hsp70 and Hsp40 partners.
molecular_function:
id: GO:0051082
label: unfolded protein binding
directly_involved_in:
- id: GO:0035966
label: response to topologically incorrect protein
locations:
- id: GO:0005829
label: cytosol
supported_by:
- reference_id: PMID:18555782
supporting_text: >-
direct interactions of substrate with Sse1p may support Hsp70-assisted protein folding
in a cooperative process
- reference_id: PMID:19165329
supporting_text: >-
including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron
specific Hsp16 (F08H9.4)
proposed_new_terms: []
knowledge_gaps:
- gap_statement: >-
Whether C. elegans HSP-110 is genetically and biochemically required for
Hsp70/Hsp40-mediated protein DISAGGREGATION in vivo, and the identity of its physiological
worm Hsp70 (HSP-1 vs STC-1 vs HSP-70) and J-protein/Hsp40 partners in that reaction, are
undetermined.
boundary: >-
It is established that HSP-110 is an HSP110-family Hsp70 NEF (conserved from yeast Sse1 to
human HSPH1) and that in neurons its loss (RNAi and the gk533 allele) increases aggregation
of misfolding-prone SOD1 alongside an Hsp70 (stc-1) and a DnaJ (dnj-19). What is NOT
established for the worm is a reconstituted or genetically defined Hsp70-Hsp40-Hsp110
disaggregase, its obligate partner set, and whether HSP-110 is required for active
dissolution of pre-formed aggregates (as opposed to preventing their formation).
gap_kind:
- BIOLOGY
dark_aspect: RESIDUAL_SUBGAP
status: OPEN
significance: >-
Metazoan protein disaggregation depends on a cooperative Hsp70-Hsp40-Hsp110 system.
Defining the worm partners and the requirement for HSP-110 would connect its molecular NEF
activity to organismal proteostasis and neuroprotection, and clarify which chaperone axis
to target in C. elegans neurodegeneration models.
resolution: >-
Tissue-specific hsp-110 loss-of-function combined with aggregation/disaggregation reporters
and photoconvertible aggregation-clearance assays; affinity-purification/mass-spectrometry
of tagged HSP-110 from worm lysate to define Hsp70/J-protein partners; in vitro
reconstitution of a worm disaggregase.
provenance:
- reference_id: PMID:19165329
supporting_text: >-
including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron
specific Hsp16 (F08H9.4)
- reference_id: PMID:16688211
supporting_text: >-
This is the first report of a nucleotide exchange activity for the Hsp110 class of
proteins
- gap_statement: >-
The endogenous C. elegans client repertoire of HSP-110 is undefined: which native
metastable proteins depend on HSP-110 NEF/holdase activity, and in which tissues, is
unknown.
boundary: >-
HSP-110 demonstrably modifies aggregation of heterologous, aggregation-prone reporters
(polyglutamine and mutant human SOD1) and, at the family level, HSP110 NEF activity
stimulates Hsp70-mediated refolding of denatured model substrates such as luciferase. No
endogenous physiological worm client of HSP-110 has been mapped.
gap_kind:
- BIOLOGY
dark_aspect: RESIDUAL_SUBGAP
status: OPEN
significance: >-
Client identity determines where HSP-110 activity is rate-limiting for proteostasis and
which phenotypes (muscle, neuron, germline, aging) are mechanistically downstream of the
NEF function.
resolution: >-
Chaperone-client capture (e.g. interactomics of tagged HSP-110, or aggregate proteomics in
hsp-110 loss-of-function) to enumerate native substrates.
provenance:
- reference_id: PMID:22242008
supporting_text: 'F08H9.3; cyn-11; cyn-12; C30C11.4; dnj-22; phb-2'
- reference_id: PMID:16688211
supporting_text: >-
The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of thermally
denatured luciferase
- gap_statement: >-
Whether HSP-110's own weak/atypical ATPase activity, and any Hsp70-independent holdase
function, have a physiological role in C. elegans is untested.
boundary: >-
The defining HSP110 NEF mechanism requires ATP BINDING but not ATP hydrolysis by HSP110,
and HSP110 does not use the canonical Hsp70 nucleotide-driven allosteric peptide-binding
cycle; direct substrate binding by Hsp110 has been observed in vitro. The in vivo relevance
of HSP-110 ATP hydrolysis and of a standalone holdase mode in the worm has not been probed.
gap_kind:
- BIOLOGY
dark_aspect: MF_DARK
status: OPEN
significance: >-
Resolving this would settle whether the IEA-propagated ATP hydrolysis activity is
functionally meaningful for HSP-110 or a fold-based over-annotation, and whether HSP-110
contributes to proteostasis independently of Hsp70.
resolution: >-
Structure-guided separation-of-function alleles (NEF-dead vs ATPase-dead vs
substrate-binding-dead) tested for rescue of hsp-110 proteostasis phenotypes in vivo, plus
in vitro ATPase and holdase assays on purified worm HSP-110.
provenance:
- reference_id: PMID:16688211
supporting_text: >-
does not require ATP hydrolysis by Sse1p
- reference_id: PMID:18555782
supporting_text: >-
does not employ the nucleotide-dependent allostery and peptide-binding mode of canonical
Hsp70s
suggested_questions:
- question: >-
Which C. elegans Hsp70 (HSP-1, STC-1, or HSP-70) and which J-domain/Hsp40 proteins form
the physiological HSP-110-dependent disaggregation machine in each tissue?
experts:
- C. elegans proteostasis biologists
- Hsp70/Hsp110 chaperone biochemists
- question: >-
Is HSP-110 required to dissolve pre-formed aggregates, or only to prevent their formation,
in worm neurons and muscle?
experts:
- Protein-aggregation/disaggregase biologists
suggested_experiments:
- experiment_type: Affinity purification / mass spectrometry
description: >-
Affinity-purify endogenously tagged HSP-110 from C. elegans lysate and identify Hsp70,
Hsp40/J-protein, and client partners to define the worm disaggregation network and native
substrates.
- experiment_type: Separation-of-function genetics
description: >-
Engineer NEF-dead, ATPase-dead, and substrate-binding-dead hsp-110 alleles and test each
for rescue of aggregation/disaggregation and lifespan phenotypes to dissect which molecular
property (nucleotide exchange, ATP hydrolysis, holdase) is required in vivo.
- experiment_type: In vitro disaggregation reconstitution
description: >-
Reconstitute disaggregation of aggregated model substrates with purified worm HSP-110,
Hsp70, and Hsp40 to test whether HSP-110 is required and rate-limiting for the reaction.