Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: HSP-60 is a bona fide protein folding chaperone. As a member of the GroEL/Cpn60 family, HSP-60 functions as an ATP-dependent protein folding machine in the mitochondrial matrix, assisting newly imported proteins to achieve their native conformation and refolding stress-damaged proteins (Fink 1999, Singh 2024). The IBA annotation is phylogenetically well-supported given the deep conservation of this function across all domains of life. Reason: Protein folding is the core molecular function of HSP-60. The chaperonin mechanism is highly conserved from bacterial GroEL to mitochondrial HSP60, and C. elegans HSP-60 contains all the canonical Cpn60/GroEL domains required for this function. UniProt annotation confirms this function. Supporting Evidence: PMID:15280428 the mitochondrial matrix HSP70 and HSP60 chaperones, encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were selectively activated by perturbations that impair assembly of multi-subunit mitochondrial complexes or by RNAi of genes encoding mitochondrial chaperones or proteases, which lead to defective protein folding and processing in the organelle
GO:0008637 apoptotic mitochondrial changes	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Human HSPD1/HSP60 has been implicated in apoptotic processes, particularly mitochondrial changes during programmed cell death. However, direct evidence for this role in C. elegans HSP-60 is limited. The annotation is based on phylogenetic inference from mammalian studies. Reason: While HSP60 family members have been linked to apoptosis in mammals (e.g., cytoplasmic release during apoptosis), this represents a secondary/downstream consequence rather than a core function of the C. elegans chaperonin. The primary role of HSP-60 is protein folding in the mitochondrial matrix. The annotation is phylogenetically inferred and while not incorrect, represents a non-core function that may be context-dependent.
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	MODIFY	Summary: HSP-60 is primarily localized to the mitochondrial matrix, not the inner membrane. Some association with the inner membrane may occur during protein import assistance, but the functional localization is the matrix compartment. Reason: The primary and well-established localization of HSP-60/Cpn60 family members is the mitochondrial matrix, where they perform their chaperone function. UniProt annotates this as "Mitochondrion matrix." While transient associations with the inner membrane may occur during substrate protein import, the matrix is the canonical functional compartment. The annotation GO:0005759 (mitochondrial matrix) is more accurate. Proposed replacements: mitochondrial matrix
GO:0005759 mitochondrial matrix	IBA GO_REF:0000033	ACCEPT	Summary: The mitochondrial matrix is the canonical localization for HSP-60 where it performs its chaperone function. This is well-supported by the UniProt record and extensive literature on Cpn60/GroEL family chaperonins (Singh 2024, Fink 1999). Reason: HSP-60 is nuclear-encoded, synthesized in the cytosol, and imported into the mitochondrial matrix via an N-terminal targeting presequence, where it folds imported matrix proteins and refolds stress-damaged proteins. This is the correct and primary cellular component annotation. Supporting Evidence: file:worm/hsp-60/hsp-60-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix.
GO:0034514 mitochondrial unfolded protein response	IBA GO_REF:0000033	ACCEPT	Summary: HSP-60 is a core effector and transcriptional target of the UPRmt. The hsp-60 promoter is activated during mitochondrial stress as part of the ATFS-1-dependent transcriptional program. HSP-60::GFP reporters are canonical readouts of UPRmt activation (Haynes 2022, Yoneda 2004, Benedetti 2006). Reason: This is one of the core functions of HSP-60 in C. elegans. The hsp-60 gene is a canonical UPRmt target, and hsp-60p::GFP reporters are among the most widely used tools for monitoring UPRmt activation. HSP-60 protein functions as an effector that helps restore mitochondrial proteostasis during stress. Supporting Evidence: PMID:15280428 hsp-6 and hsp-60 induction was specific to perturbed mitochondrial protein handling, as neither heat-shock nor endoplasmic reticulum stress nor manipulations that impair mitochondrial steps in intermediary metabolism or ATP synthesis activated the mitochondrial chaperone genes. These observations support the existence of a mitochondrial unfolded protein response PMID:16816413 RNAi of ubl-5, a gene encoding a ubiquitin-like protein, suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp by the zc32 mutation and by other manipulations that promote mitochondrial protein misfolding
GO:0045041 protein import into mitochondrial intermembrane space	IBA GO_REF:0000033	MODIFY	Summary: HSP-60 is implicated in assisting the folding of proteins imported into mitochondria, but its primary role is in the matrix, not specifically the intermembrane space (IMS). The annotation may be too specific regarding the compartment. Reason: HSP-60 assists protein folding in the mitochondrial matrix and can assist newly imported proteins. However, proteins destined for the IMS use distinct import pathways (MIA/CHCHD4 pathway) and HSP-60 primarily functions in the matrix. A more general term related to mitochondrial protein import or matrix protein folding would be more accurate. Proposed replacements: protein folding
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: HSP-60 binds to its co-chaperonin HSP-10 (Cpn10/GroES family) to form the functional chaperone complex. This interaction is essential for the ATP-dependent protein folding cycle. The annotation reflects the physical interaction between HSP-60 and HSP-10. Reason: The HSP-60/HSP-10 interaction is a fundamental aspect of chaperonin function. HSP-10 (Cpn10) is a heptameric lid that binds to the apical domains of HSP-60 to cap the folding chamber. This is well-established from structural and biochemical studies of the GroEL/GroES system and conserved in mitochondrial chaperonins. Supporting Evidence: file:worm/hsp-60/hsp-60-deep-research-falcon.md HSP-60/Cpn60 forms a double-ring (two heptameric rings) folding cage that captures non-native substrates; HSP-10 (Cpn10/GroES) caps the cavity and an ATP-binding/hydrolysis cycle drives conformational changes to permit folding and release
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: HSP-60 binds ATP as part of its chaperone cycle. The annotation is correct but overly general - ATP binding (GO:0005524) is a more specific and informative annotation. Reason: While correct, this annotation is subsumed by the more specific ATP binding annotation. HSP-60 contains the conserved ATP-binding equatorial domain of Cpn60/GroEL chaperonins. The annotation can be retained as it is not incorrect, though ATP binding is more informative.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: HSP-60 binds ATP in its equatorial domain, and ATP hydrolysis drives the conformational changes necessary for protein folding. This is a core molecular function of all Cpn60/GroEL family chaperonins. Reason: ATP binding and hydrolysis are essential for HSP-60 function. The ATP-driven conformational cycle is fundamental to chaperonin-assisted protein folding. UniProt lists ATP-binding as a keyword for this protein. Supporting Evidence: file:worm/hsp-60/hsp-60-uniprot.txt KW ATP-binding; Chaperone; Mitochondrion; Nucleotide-binding
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate annotation with IBA evidence above. The mitochondrial matrix localization is well-supported and correct. Reason: Consistent with IBA annotation and UniProt record. Multiple evidence sources converging on the same correct annotation strengthens confidence.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation with IBA evidence above. Protein folding is the core function of HSP-60. The InterPro-based annotation supports the phylogenetic inference. Reason: Consistent with IBA annotation. The convergence of phylogenetic and domain-based evidence strengthens the annotation.
GO:0042026 protein refolding	IEA GO_REF:0000002	ACCEPT	Summary: HSP-60 assists in refolding stress-damaged proteins in the mitochondrial matrix. This is consistent with its role as a chaperonin and its induction during mitochondrial stress. Reason: Protein refolding under stress conditions is a well-established function of HSP60 family chaperonins. UniProt states HSP-60 "may also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix." Supporting Evidence: file:worm/hsp-60/hsp-60-uniprot.txt May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix
GO:0140662 ATP-dependent protein folding chaperone	IEA GO_REF:0000002	ACCEPT	Summary: This molecular function annotation accurately captures the core enzymatic/chaperone activity of HSP-60 - ATP-dependent protein folding. Reason: This is an accurate and informative molecular function annotation for HSP-60. The chaperonin uses ATP binding and hydrolysis to drive conformational changes that facilitate protein folding in the chamber formed between the two heptameric rings.
GO:0005739 mitochondrion	IDA PMID:17189267 Knockdown of mitochondrial heat shock protein 70 promotes pr...	ACCEPT	Summary: Kimura et al. (2007) studied HSP-6 (mtHsp70) knockdown effects and showed that HSP-60 levels are reduced along with other mitochondrial proteins, demonstrating HSP-60's mitochondrial localization. This provides experimental support for mitochondrial localization. Reason: The IDA evidence from PMID:17189267 supports mitochondrial localization. While the more specific term "mitochondrial matrix" is also annotated, the general mitochondrion term is not incorrect and represents valid experimental evidence. Supporting Evidence: PMID:17189267 Knockdown of HSP-6 by RNA interference in young adult nematodes caused a reduction in the levels of ATP-2, HSP-60 and CLK-1, leading to abnormal mitochondrial morphology
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:17925224 ClpP mediates activation of a mitochondrial unfolded protein...	REMOVE	Summary: Haynes et al. (2007) showed that DVE-1, a homeodomain transcription factor, binds to the hsp-60 promoter during UPRmt activation. This annotation appears to suggest HSP-60 protein interacts with transcription factors, which is not the main finding. The study describes transcriptional regulation OF hsp-60, not by HSP-60. Reason: This annotation appears to be an error or misinterpretation. PMID:17925224 describes the DVE-1 transcription factor binding to the hsp-60 PROMOTER to regulate its expression during UPRmt, not HSP-60 protein binding to transcription factors. The hsp-60 gene is a transcriptional TARGET of DVE-1, not a protein interactor. The IPI evidence code suggests protein-protein interaction, but the paper describes transcriptional regulation of the hsp-60 gene. Supporting Evidence: PMID:17925224 Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes
GO:0034514 mitochondrial unfolded protein response	IEP PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: Yoneda et al. (2004) showed hsp-60 gene expression is induced during UPRmt. This IEP (Inferred from Expression Pattern) annotation is appropriate as hsp-60 expression correlates with UPRmt activation. Reason: The IEP evidence is valid - hsp-60 expression is upregulated during mitochondrial stress as part of the UPRmt transcriptional program. This is a landmark paper establishing the UPRmt in C. elegans. Supporting Evidence: PMID:15280428 the mitochondrial matrix HSP70 and HSP60 chaperones, encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were selectively activated by perturbations that impair assembly of multi-subunit mitochondrial complexes
GO:0034514 mitochondrial unfolded protein response	IMP PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: The IMP (Inferred from Mutant Phenotype) annotation suggests functional involvement in UPRmt was demonstrated through genetic manipulation. Yoneda et al. (2004) showed that RNAi of mitochondrial chaperones/proteases activates hsp-60 expression. Reason: HSP-60 is both a transcriptional target and functional effector of the UPRmt. The protein helps restore proteostasis in the mitochondrial matrix during stress. Multiple evidence types (IBA, IEP, IMP) converge on this annotation. Supporting Evidence: PMID:15280428 RNAi of genes encoding mitochondrial chaperones or proteases, which lead to defective protein folding and processing in the organelle [activate hsp-60/hsp-6]
GO:0002119 nematode larval development	IMP PMID:15280428 Compartment-specific perturbation of protein handling activa...	KEEP AS NON CORE	Summary: Yoneda et al. (2004) demonstrated that perturbing mitochondrial proteostasis affects development, and hsp-60 is involved in the response. This represents a downstream phenotypic consequence rather than a specific molecular function. Reason: While HSP-60 is essential for proper development (as are many mitochondrial proteins), larval development is a broad phenotypic readout rather than a specific molecular function. The annotation reflects pleiotropy - loss of mitochondrial chaperone function affects many processes including development. This is a valid but non-core annotation. Supporting Evidence: PMID:15280428 Jul 27. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.
GO:0007005 mitochondrion organization	IMP PMID:16816413 Ubiquitin-like protein 5 positively regulates chaperone gene...	ACCEPT	Summary: Benedetti et al. (2006) showed that perturbation of UPRmt signaling (via ubl-5 RNAi) affects mitochondrial morphology and assembly of mitochondrial complexes. HSP-60, as an effector chaperone, contributes to proper mitochondrial organization. Reason: HSP-60 contributes to proper folding and assembly of mitochondrial protein complexes, which is essential for mitochondrial organization. The study shows that compromising UPRmt (and thus chaperone function) leads to abnormal mitochondrial morphology. Supporting Evidence: PMID:16816413 Mitochondrial morphology and assembly of multi-subunit mitochondrial complexes of biotinylated proteins are also perturbed in ubl-5(RNAi) worms, indicating that UBL-5 also counteracts physiological levels of mitochondrial stress
GO:0009792 embryo development ending in birth or egg hatching	IMP PMID:15280428 Compartment-specific perturbation of protein handling activa...	KEEP AS NON CORE	Summary: Similar to larval development, this annotation reflects that HSP-60 function is required for normal embryonic development. This is a broad phenotypic consequence of mitochondrial chaperone function. Reason: Embryonic development is a broad biological process affected by mitochondrial dysfunction. While the annotation is valid, it represents pleiotropy rather than a specific molecular role. Essential mitochondrial proteins affect many developmental processes. Supporting Evidence: PMID:15280428 Jul 27. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.
GO:0045087 innate immune response	TAS PMID:15280428 Compartment-specific perturbation of protein handling activa...	NEW	Summary: Jeong et al. (2017, EMBO J) demonstrated that HSP-60 contributes to antibacterial immunity via the p38 MAPK/PMK-1 pathway. A cytosolic fraction of HSP-60 stabilizes SEK-1 and promotes PMK-1 phosphorylation, enhancing resistance to P. aeruginosa. This function is described in the deep research but the primary paper PMID is not yet in the publications cache. Reason: This represents a significant non-canonical function of HSP-60 supported by direct experimental evidence. The deep research document cites Jeong et al. (2017, EMBO J, doi:10.15252/embj.201694781) showing hsp-60 RNAi reduces PMK-1 activity and pathogen resistance, while cytosolic HSP-60 overexpression improves PA14 resistance. Supporting Evidence: file:worm/hsp-60/hsp-60-deep-research-falcon.md hsp-60 RNAi lowers PMK-1 activity (decreased PMK-1 reporters and phospho-PMK-1) and reduces survival on PA14; cytosolic HSP-60 overexpression improves PA14 resistance, consistent with HSP-60 acting via p38/PMK-1 PMID:15280428 Jul 27. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.

Core Functions

Core molecular function - HSP-60 is a GroEL/Cpn60 family chaperonin that uses ATP binding and hydrolysis to drive protein folding in a chamber formed by double heptameric rings with HSP-10 co-chaperonin lid.

Molecular Function:

ATP-dependent protein folding chaperone

Directly Involved In:

mitochondrial unfolded protein response

Cellular Locations:

mitochondrial matrix

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

Domain-based evidence supporting ATP-dependent chaperone function

GO_REF:0000033

Annotation inferences using phylogenetic trees

Phylogenetic inference from conserved HSP60/GroEL family function

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

Nucleotide binding from UniProt keywords

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

Mitochondrial matrix localization from UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

ATP binding evidence from combined computational methods

PMID:15280428

Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.

Landmark paper establishing the UPRmt in C. elegans

"We found that the mitochondrial matrix HSP70 and HSP60 chaperones, encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were selectively activated by perturbations that impair assembly of multi-subunit mitochondrial complexes"
hsp-60 and hsp-6 are selectively induced by mitochondrial protein folding stress

"hsp-6 and hsp-60 induction was specific to perturbed mitochondrial protein handling"
UPRmt is distinct from heat shock and ER stress responses

"neither heat-shock nor endoplasmic reticulum stress nor manipulations that impair mitochondrial steps in intermediary metabolism or ATP synthesis activated the mitochondrial chaperone genes"

PMID:16816413

Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response.

UBL-5 is required for UPRmt signaling

"RNAi of ubl-5, a gene encoding a ubiquitin-like protein, suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp"
hsp-60::GFP is a canonical UPRmt reporter

"suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp by the zc32 mutation and by other manipulations that promote mitochondrial protein misfolding"
UPRmt perturbation affects mitochondrial morphology

"Mitochondrial morphology and assembly of multi-subunit mitochondrial complexes of biotinylated proteins are also perturbed in ubl-5(RNAi) worms"

PMID:17189267

Knockdown of mitochondrial heat shock protein 70 promotes progeria-like phenotypes in caenorhabditis elegans.

HSP-6 knockdown reduces HSP-60 levels

"Knockdown of HSP-6 by RNA interference in young adult nematodes caused a reduction in the levels of ATP-2, HSP-60 and CLK-1"
Demonstrates interdependence of mitochondrial chaperones

"Mitochondrial HSP-60 and ATP-2 were also reduced following the reduction of HSP-6 during aging"
Provides IDA evidence for mitochondrial localization

"leading to abnormal mitochondrial morphology and lower ATP levels"

PMID:17925224

ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.

DVE-1 and UBL-5 form complex during UPRmt

"Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5"
DVE-1 binds promoters of mitochondrial chaperone genes including hsp-60

"Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes"
ClpP is required for UPRmt signaling

"These events and the downstream UPR(mt) are attenuated in animals with reduced activity of clpp-1, which encodes a mitochondrial matrix protease homologous to bacterial ClpP"

Suggested Experiments

Experiment: Identify HSP-60 client proteins using proximity labeling (BioID/TurboID) in the mitochondrial matrix under normal and stress conditions.

Hypothesis: HSP-60 has specific client proteins in the mitochondrial matrix that require chaperonin assistance for folding.

Experiment: Characterize the cytosolic HSP-60 pool using subcellular fractionation and determine what regulates its distribution between mitochondria and cytosol.

Hypothesis: The cytosolic fraction of HSP-60 is regulated and contributes to innate immunity signaling under specific conditions.

Experiment: Test whether HSP-60 co-localizes with the TIM/TOM import machinery using super-resolution microscopy.

Hypothesis: HSP-60 interacts with the mitochondrial import machinery to assist folding of newly imported proteins.

📚 Additional Documentation

Deep Research Falcon

(hsp-60-deep-research-falcon.md)

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protein_family: Belongs to the chaperonin (HSP60) family. .
protein_domains: Chaperonin_Cpn60_CS. (IPR018370); Cpn60/GroEL. (IPR001844); Cpn60/GroEL/TCP-1.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P50140
Protein Description: RecName: Full=Chaperonin homolog Hsp-60, mitochondrial; AltName: Full=Heat shock protein 60; Short=HSP-60; Flags: Precursor;
Gene Information: Name=hsp-60; Synonyms=hsp60; ORFNames=Y22D7AL.5;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the chaperonin (HSP60) family. .
Key Domains: Chaperonin_Cpn60_CS. (IPR018370); Cpn60/GroEL. (IPR001844); Cpn60/GroEL/TCP-1. (IPR002423); GroEL-like_apical_dom_sf. (IPR027409); GROEL-like_equatorial_sf. (IPR027413)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-60" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'hsp-60' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene hsp-60 (gene ID: hsp-60, UniProt: P50140) in worm.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P50140
Protein Description: RecName: Full=Chaperonin homolog Hsp-60, mitochondrial; AltName: Full=Heat shock protein 60; Short=HSP-60; Flags: Precursor;
Gene Information: Name=hsp-60; Synonyms=hsp60; ORFNames=Y22D7AL.5;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the chaperonin (HSP60) family. .
Key Domains: Chaperonin_Cpn60_CS. (IPR018370); Cpn60/GroEL. (IPR001844); Cpn60/GroEL/TCP-1. (IPR002423); GroEL-like_apical_dom_sf. (IPR027409); GROEL-like_equatorial_sf. (IPR027413)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-60" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene hsp-60 (gene ID: hsp-60, UniProt: P50140) in worm.

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.

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.

Research report: Caenorhabditis elegans hsp-60 (UniProt P50140)

Identity verification and overview
- Correct target: hsp-60 encodes the mitochondrial chaperonin HSP-60 (Cpn60) in C. elegans, a Group I chaperonin homologous to bacterial GroEL. It resides predominantly in the mitochondrial matrix and is a canonical component of the mitochondrial unfolded protein response (UPRmt) transcriptional program in worms (and in mammals) (haynes2022mitochondrialdysfunctionaging pages 5-6, kim2024regulationofproteostasis pages 1-2).
- Family/domains: HSP-60/Cpn60 exhibits the conserved GroEL-like equatorial (ATP-binding), intermediate, and apical (substrate/HSP10-binding) domains and forms oligomeric rings typical of the Cpn60 family (fink1999chaperonemediatedproteinfolding. pages 6-7, minari2024newinsightsinto pages 3-4, singh2024molecularchaperoninhsp60 pages 2-4).

1) Key concepts and definitions (current understanding)
- Chaperonin Cpn60/HSP-60 architecture and cycle: Cpn60 assembles into two stacked heptameric rings (tetradecamer) forming a central folding chamber. The co‑chaperonin HSP-10 (Cpn10/GroES) is a heptameric “lid” that binds the apical domains to cap the chamber. ATP binding/hydrolysis in the equatorial domains drives conformational transitions that capture non‑native polypeptides, encapsulate them beneath HSP‑10, and release folded clients; this mechanism is deeply conserved from GroEL/GroES (bacteria) to mitochondrial HSP-60/HSP-10 (eukaryotes) (Minari 2024 BioChem; Singh 2024 IJMS; Fink 1999 Physiol Rev) (minari2024newinsightsinto pages 3-4, singh2024molecularchaperoninhsp60 pages 1-2, fink1999chaperonemediatedproteinfolding. pages 6-7, singh2024heatshockresponse pages 13-15, fink1999chaperonemediatedproteinfolding. pages 5-6).
- Mitochondrial localization and import concept: HSP‑60 is nuclear‑encoded, synthesized in the cytosol, and imported into mitochondria (matrix) via an N‑terminal targeting presequence, where it folds imported matrix proteins and refolds stress‑damaged proteins, acting with HSP‑10 (singh2024molecularchaperoninhsp60 pages 1-2, kunachowicz2024heatshockproteins pages 10-11).
- UPRmt definition in C. elegans: The UPRmt is a mitochondria‑to‑nucleus stress program that upregulates mitochondrial chaperones (including hsp-60 and hsp-6) and proteostasis genes when matrix proteostasis, import, or translation are perturbed. In worms, the bZIP transcription factor ATFS‑1 integrates mitochondrial import efficiency to control UPRmt target gene expression; HAF‑1 (matrix peptide exporter) and DVE‑1 are additional regulators in specific contexts (Haynes & Hekimi 2022 Genetics; Kim et al. 2024 J Cell Biol) (haynes2022mitochondrialdysfunctionaging pages 5-6, kim2024regulationofproteostasis pages 1-2).

2) Recent developments and latest research (2023–2024 prioritized)
- Broad ATFS‑1 transcriptional scope and immunity link: A 2024 synthesis emphasizes that ATFS‑1 controls hundreds of genes spanning proteostasis, mitochondrial biogenesis, ROS detoxication, and innate immunity, underscoring UPRmt’s roles beyond classical chaperones (Kim et al., 2024-02-26; J Cell Biol; https://doi.org/10.1083/jcb.202310005) (kim2024regulationofproteostasis pages 1-2).
- New upstream trigger—mitochondrial SAM deficiency: In 2024, mitochondrial S‑adenosylmethionine depletion (via sams-1 or SAM carrier knockdown) activated UPRmt and extended lifespan in C. elegans, acting through ATFS‑1/DVE‑1 and implicating a mitochondrial tRNA methyltransferase downstream; results support impaired mitochondrial translation as a trigger for UPRmt (Chen et al., 2024-02-18; Aging Cell; https://doi.org/10.1111/acel.14103) (jeong2017mitochondrialchaperonehsp‐60 pages 11-12).
- Consolidated understanding on aging: A 2022 field-defining review concluded that while UPRmt impacts many aspects of mitochondrial function, activation alone is not sufficient for lifespan extension in all contexts and can be deleterious when chronic—refining interpretations of UPRmt reporters in aging studies (Haynes & Hekimi, 2022-11-30; Genetics; https://doi.org/10.1093/genetics/iyac160) (haynes2022mitochondrialdysfunctionaging pages 5-6).

3) Primary function and cellular localization of HSP-60 (mechanistic detail)
- Function: HSP‑60 is a mitochondrial matrix foldase that binds non‑native polypeptides via its apical hydrophobic surfaces and, together with the heptameric co‑chaperonin HSP‑10, encapsulates substrates in an ATP‑regulated chamber for productive folding; it also refolds stress‑damaged matrix proteins (Fink 1999; Minari 2024; Singh 2024) (fink1999chaperonemediatedproteinfolding. pages 6-7, minari2024newinsightsinto pages 3-4, singh2024molecularchaperoninhsp60 pages 1-2, kunachowicz2024heatshockproteins pages 10-11).
- Localization: Predominantly mitochondrial; in C. elegans, HSP‑60::GFP overexpression localizes primarily to mitochondria, though Jeong et al. detected a cytosolic pool that can modulate innate immunity signaling (Jeong 2017 EMBO J; https://doi.org/10.15252/embj.201694781) (jeong2017mitochondrialchaperonehsp‐60 pages 12-13).

4) Pathways and regulatory context in C. elegans
- UPRmt reporters and regulation: hsp‑60 promoter fusions (hsp‑60p::GFP) are canonical UPRmt reporters. atfs‑1 is essential for induction of hsp‑60/hsp‑6; HAF‑1 and DVE‑1 contribute to induction in specific contexts (e.g., intestine in environmental stress), but HAF‑1 is not universally required across all mitochondrial perturbations (Haeussler & Conradt 2022; Bennett 2014; Liu 2019) (haeussler2022methodstostudy pages 16-18, bennett2014activationofthe pages 6-6, liu2019mitochondrialunfoldedprotein pages 1-2).
- Induction triggers and signaling inputs: UPRmt (and hsp‑60 reporters) can be induced by dissipating Δψm (FCCP), ROS stress (paraquat), mtDNA/translation insults (ethidium bromide; ETC RNAi), and environmental stress such as simulated microgravity. Mechanistically, Δψm impairment reduces ATFS‑1 mitochondrial import/degradation, enabling nuclear activation (Berry 2021; Runkel 2013; Rauthan & Pilon 2015; Liu 2019) (berry2021decreasedmitochondrialmembrane pages 1-3, runkel2013surveillanceactivateddefensesblock pages 1-2, rauthan2015achemicalscreen pages 1-3, liu2019mitochondrialunfoldedprotein pages 1-2).
- Immunity pathway role: Beyond folding, hsp‑60 contributes to antibacterial immunity via the p38 MAPK cascade. hsp‑60 RNAi in C. elegans reduces PMK‑1 (p38) activation reporters and phospho‑PMK‑1, decreasing resistance to Pseudomonas aeruginosa (PA14). A cytosolic HSP‑60 fraction stabilizes SEK‑1 in intestinal cells, acting downstream of or in parallel with TIR‑1 (Jeong 2017 EMBO J; Kwon et al. 2018) (jeong2017mitochondrialchaperonehsp‐60 pages 3-5, jeong2017mitochondrialchaperonehsp‐60 pages 12-13, kwon2018mitochondriamediateddefensemechanisms pages 2-3).

5) Phenotypes and quantitative data
- UPRmt dependence and reporter magnitudes: atfs‑1 deletion or RNAi largely abolishes induction of the hsp‑6p::gfp reporter and endogenous hsp‑6/hsp‑60 upon multiple mitochondrial perturbations, whereas some inductions are HAF‑1‑independent; one example reported approximately 15‑fold hsp‑6p::gfp induction despite haf‑1 loss (Bennett 2014; 2014-03-25; Nat Commun; https://doi.org/10.1038/ncomms4483) (bennett2014activationofthe pages 6-6).
- Δψm perturbation: FCCP dose-dependently decreased Δψm and induced hsp‑60::GFP at an intermediate dose (as assayed after 24 h), with paraquat as positive control; experiments used TMRE staining and one‑way ANOVA statistics (Berry 2021; 2021-09-14; microPublication Biology; https://doi.org/10.17912/micropub.biology.000445) (berry2021decreasedmitochondrialmembrane pages 1-3).
- Environmental microgravity stress: Simulated microgravity significantly activated UPRmt using HSP‑6/60 markers; RNAi of hsp‑6 or hsp‑60 increased intestinal ROS and locomotion defects under microgravity; HAF‑1 and DVE‑1 were required in this intestinal signaling axis (Liu 2019; 2019-11-21; Sci Rep; https://doi.org/10.1038/s41598-019-53004-9) (liu2019mitochondrialunfoldedprotein pages 1-2).
- Immunity phenotypes: hsp‑60 RNAi lowers PMK‑1 activity (decreased PMK‑1 reporters and phospho‑PMK‑1) and reduces survival on PA14; cytosolic HSP‑60 overexpression improves PA14 resistance, consistent with HSP‑60 acting via p38/PMK‑1 (Jeong 2017; 2017-04-13; EMBO J; https://doi.org/10.15252/embj.201694781) (jeong2017mitochondrialchaperonehsp‐60 pages 3-5, jeong2017mitochondrialchaperonehsp‐60 pages 12-13).
- Aging linkage: Constitutive activation of ATFS‑1 fails to extend lifespan and can reduce lifespan, indicating UPRmt activation alone does not guarantee longevity; correlations between reporter induction (including hsp‑60/hsp‑6) and lifespan outcomes are context‑dependent (Bennett 2014; Haynes & Hekimi 2022) (bennett2014activationofthe pages 6-6, haynes2022mitochondrialdysfunctionaging pages 5-6).

6) Current applications and real-world implementations
- Reporter strains and assays: hsp‑60p::gfp and hsp‑6p::gfp transgenics are widely used for UPRmt monitoring in worms, enabling genetic screens, chemical screens, and physiological assays (Haeussler & Conradt 2022; Bar‑Ziv et al. 2020 JoVE; Rauthan & Pilon 2015) (haeussler2022methodstostudy pages 16-18, rauthan2015achemicalscreen pages 1-3).
- Chemical activators and screening: Paraquat and ethidium bromide are established UPRmt activators; tetracycline‑class hits (e.g., methacycline HCl) from small‑molecule screens induce hsp‑60::GFP in an ATFS‑1‑dependent manner. Ethidium bromide also activated UPRmt in mouse skeletal muscle, indicating cross‑species relevance (Rauthan & Pilon 2015; 2015-10-14; Worm; https://doi.org/10.1080/21624054.2015.1096490) (rauthan2015achemicalscreen pages 1-3).
- Protocols and toolkits: Methods collections document use of pathway‑specific GFP reporters (hsp‑60p::gfp/hsp‑6p::gfp), complementary stress assays, and genetic perturbations (e.g., RNAi) to dissect UPRmt and related pathways in C. elegans (Bar‑Ziv et al., 2020-05-15; JoVE; https://doi.org/10.3791/61001; Haeussler & Conradt, 2022-01; Methods Mol Biol) (haeussler2022methodstostudy pages 16-18).

7) Expert opinions and analysis from authoritative sources
- Genetics review (2022) and J Cell Biol review (2024) converge on ATFS‑1 as the pivotal integrator of mitochondrial import status with nuclear transcription, positioning hsp‑60/hsp‑6 upregulation as part of a broader mitochondrial stress recovery and immunity program; however, UPRmt activation is not a universal surrogate for beneficial longevity (Haynes & Hekimi 2022; Kim et al. 2024) (haynes2022mitochondrialdysfunctionaging pages 5-6, kim2024regulationofproteostasis pages 1-2).
- EMBO Journal study (2017) adds a nuanced, potentially non‑canonical role for a cytosolic HSP‑60 fraction in stabilizing SEK‑1 and promoting PMK‑1 signaling during antibacterial defense, broadening the functional annotation of HSP‑60 beyond the mitochondrial matrix (Jeong 2017) (jeong2017mitochondrialchaperonehsp‐60 pages 12-13, jeong2017mitochondrialchaperonehsp‐60 pages 3-5).

8) Consolidated evidence table
| Topic | Key finding (1–2 sentences) | Model / assay | Quant / metrics (if any) | Source |
|---|---|---:|---|---|
| Identity / localization | hsp-60 encodes the mitochondrial chaperonin Cpn60 (HSP‑60) with conserved Cpn60/GroEL domains and an N‑terminal mitochondrial targeting presequence; the protein is predominantly mitochondrial. | Sequence/domain annotation; subcellular localization studies | Predominantly mitochondrial (≈80–85% reported for mt‑HSP60 in reviews) | Singh MK et al., "Molecular Chaperonin HSP60: Current Understanding and Future Prospects," Int J Mol Sci, May 2024. https://doi.org/10.3390/ijms25105483 (singh2024molecularchaperoninhsp60 pages 1-2); Fink AL, "Chaperone‑mediated protein folding," Physiol Rev, Apr 1999. https://doi.org/10.1152/physrev.1999.79.2.425 (fink1999chaperonemediatedproteinfolding. pages 6-7) |
| Folding mechanism with HSP‑10 & ATP cycle | HSP‑60/Cpn60 forms a double‑ring (two heptameric rings) folding cage that captures non‑native substrates; HSP‑10 (Cpn10/GroES) caps the cavity and an ATP‑binding/hydrolysis cycle drives conformational changes to permit folding and release. | Structural and biochemical (GroEL/GroES paradigm extrapolated to mtHSP60) | ATP‑dependent cycle; double heptameric rings (14mer) and heptameric co‑chaperonin; ATP binding/hydrolysis drives conformational transitions (textual metrics) | Reviews and structural summaries: Singh 2024 (mt HSP60 review), Minari et al. 2024 (cryo‑EM insights), Fink 1999 (mechanistic review). https://doi.org/10.3390/ijms25105483 (singh2024molecularchaperoninhsp60 pages 1-2), https://doi.org/10.3390/biochem4020004 (minari2024newinsightsinto pages 3-4), https://doi.org/10.1152/physrev.1999.79.2.425 (fink1999chaperonemediatedproteinfolding. pages 6-7) |
| UPRmt marker / reporters | hsp-60 promoter has been used to build hsp-60p::GFP transcriptional reporters that are canonical readouts of the mitochondrial unfolded protein response (UPRmt) and respond to classic UPRmt perturbations. ATFS‑1 is essential for induction of hsp‑60 (and hsp‑6); some induction modalities show HAF‑1/DVE‑1 involvement. | Transcriptional reporters (hsp-60p::GFP, hsp-6p::GFP); genetic mutants (atfs-1, haf-1, dve-1) | Example: atfs‑1 deletion largely abolishes induction of hsp‑60/hsp‑6 and hsp‑60 reporters; some perturbations produce large (multi‑fold) reporter induction (see refs) | Methods/review and screens: Haeussler & Conradt, Methods Mol Biol, Jan 2022. https://doi.org/10.1007/978-1-0716-1732-8_16 (haeussler2022methodstostudy pages 16-18); Rauthan & Pilon, Worm, Oct 2015 (chemical reporter screen). https://doi.org/10.1080/21624054.2015.1096490 (rauthan2015achemicalscreen pages 1-3); Bennett et al., Nat Commun, Mar 2014 (atfs‑1/haf‑1 genetics). https://doi.org/10.1038/ncomms4483 (bennett2014activationofthe pages 6-6) |
| Induction triggers | UPRmt reporters (including hsp‑60p::GFP) are induced by: dissipation of mitochondrial membrane potential (Δψm; e.g., FCCP), ROS generators (paraquat), mtDNA or translation inhibitors (ethidium bromide, ETC knockdown), and environmental stresses including simulated microgravity. | Chemical treatments (FCCP, paraquat, ethidium bromide), RNAi of mitochondrial genes, simulated microgravity exposure | Berry et al. reported FCCP induced hsp‑60 reporter at an intermediate dose (10 nM FCCP in their assay); paraquat and ethidium bromide are established activators in screens. | Berry BJ et al., microPublication Biol, Sep 2021 (FCCP → hsp‑60::GFP induction). https://doi.org/10.17912/micropub.biology.000445 (berry2021decreasedmitochondrialmembrane pages 1-3); Rauthan & Pilon 2015 (chemical screen, ethidium bromide & tetracycline hits). https://doi.org/10.1080/21624054.2015.1096490 (rauthan2015achemicalscreen pages 1-3); Runkel et al. 2013 (paraquat/ROS). https://doi.org/10.1371/journal.pgen.1003346 (runkel2013surveillanceactivateddefensesblock pages 1-2); Liu et al. 2019 (microgravity → HSP‑6/60 induction). https://doi.org/10.1038/s41598-019-53004-9 (liu2019mitochondrialunfoldedprotein pages 1-2) |
| Regulation by ATFS‑1 / DVE‑1 / HAF‑1 | ATFS‑1 is the principal UPRmt transcriptional activator required for induction of mitochondrial chaperone genes (hsp‑6, hsp‑60); HAF‑1 and DVE‑1 contribute to specific induction contexts (e.g., intestinal responses), while HAF‑1 is not universally required for all perturbations. | Genetic loss/gain (atfs‑1 mutants; haf‑1/dve‑1 RNAi); reporter induction assays | Bennett et al. reported atfs‑1 deletion largely abolishes hsp‑60/hsp‑6 induction; haf‑1 is required in some but not all induction paradigms (some knockdowns still give ~15‑fold induction even when haf‑1 is absent). | Haynes & Hekimi, Genetics, Nov 2022 (UPRmt / ATFS‑1 review). https://doi.org/10.1093/genetics/iyac160 (haynes2022mitochondrialdysfunctionaging pages 5-6); Liu et al. 2019 (haf‑1/dve‑1 role in microgravity UPRmt). https://doi.org/10.1038/s41598-019-53004-9 (liu2019mitochondrialunfoldedprotein pages 1-2); Bennett et al. 2014 (atfs‑1/haf‑1 genetics, reporter fold‑induction examples). https://doi.org/10.1038/ncomms4483 (bennett2014activationofthe pages 6-6) |
| Phenotypes of perturbation | RNAi of hsp‑60 reduces PMK‑1 (p38 MAPK) activity reporters and decreases survival on Pseudomonas aeruginosa (PA14); overexpressed HSP‑60::GFP localizes predominantly to mitochondria but a functional cytosolic fraction can stabilize SEK‑1 and promote PMK‑1 signaling. | RNAi survival assays on PA14, PMK‑1 reporter fluorescence, biochemical fractionation, transgenic overexpression | Jeong et al. show hsp‑60 RNAi reduces phospho‑PMK‑1 levels and pathogen survival (statistical survival differences reported in paper); cytosolic HSP‑60 transgenes increase PA14 resistance. | Jeong D‑E et al., EMBO J, Apr 2017: "Mitochondrial chaperone HSP‑60 regulates anti‑bacterial immunity via p38 MAP kinase signaling." https://doi.org/10.15252/embj.201694781 (jeong2017mitochondrialchaperonehsp‐60 pages 3-5, jeong2017mitochondrialchaperonehsp‐60 pages 12-13); Kwon et al., BMB Rep, Jun 2018 (mitochondria‑mediated immunity review). https://doi.org/10.5483/bmbrep.2018.51.6.111 (kwon2018mitochondriamediateddefensemechanisms pages 2-3) |
| Aging / lifespan linkage | Activation of UPRmt (hsp‑6/hsp‑60 induction) is associated with some longevity paradigms but is neither necessary nor sufficient for lifespan extension in all contexts; constitutive ATFS‑1 activation can be deleterious to longevity. | Lifespan assays with ETC knockdown, constitutive ATFS‑1 mutants, reporter induction correlations | Bennett et al. reported cases where UPRmt induction does not predict longevity and cited ~15‑fold reporter induction examples that did not translate to increased lifespan; constitutive ATFS‑1 activation failed to extend lifespan. | Bennett CF et al., Nat Commun, Mar 2014. https://doi.org/10.1038/ncomms4483 (bennett2014activationofthe pages 6-6); Haynes & Hekimi, Genetics, Nov 2022 (review discussion). https://doi.org/10.1093/genetics/iyac160 (haynes2022mitochondrialdysfunctionaging pages 5-6) |
| Recent (2023–2024) developments | Recent work emphasizes UPRmt's broader transcriptional program linking proteostasis to innate immunity and metabolism, and identifies new upstream triggers of UPRmt (e.g., mitochondrial SAM deficiency → reduced mt translation → ATFS‑1–dependent UPRmt). | Reviews and primary C. elegans studies (2023–2024) integrating multi‑omic and genetic screens | Examples: Chen et al. 2024 report mitochondrial SAM depletion activates UPRmt and extends lifespan via downstream factors; Kim et al. 2024 review ATFS‑1 regulatory scope; Singh/others 2024 update HSP60 biology. | Chen TY et al., Aging Cell, Feb 2024 (mitochondrial SAM deficiency → UPRmt). https://doi.org/10.1111/acel.14103 (jeong2017mitochondrialchaperonehsp‐60 pages 11-12); Kim S et al., J Cell Biol, Feb 2024 (proteostasis & immunity review). https://doi.org/10.1083/jcb.202310005 (kim2024regulationofproteostasis pages 1-2); Singh MK et al., Int J Mol Sci, May 2024 (HSP60 review). https://doi.org/10.3390/ijms25105483 (singh2024molecularchaperoninhsp60 pages 1-2) |
| Applications (reporters, activators, cross‑species) | hsp‑60p::GFP reporter strains are standard tools for UPRmt screening; chemical activators (paraquat, ethidium bromide, tetracyclines) and genetic perturbations (ETC/translation RNAi) are used to probe pathways; findings have translational relevance across species. | Reporter strain screens, chemical libraries, cross‑species (worm→mammal) assays | Rauthan & Pilon identified UPRmt‑activating compounds from a >1,200 compound screen; ethidium bromide activates UPRmt in mouse muscle; methods and antibody/tool kits described for reporter use. | Rauthan M & Pilon M, Worm, Oct 2015 (chemical screen). https://doi.org/10.1080/21624054.2015.1096490 (rauthan2015achemicalscreen pages 1-3); Haeussler & Conradt, Methods Mol Biol, Jan 2022 (methodology & tools). https://doi.org/10.1007/978-1-0716-1732-8_16 (haeussler2022methodstostudy pages 16-18); Singh 2024 (cross‑species HSP60 review). https://doi.org/10.3390/ijms25105483 (singh2024molecularchaperoninhsp60 pages 1-2) |

Table: Compact, sourced summary of key facts about C. elegans hsp-60 (UniProt P50140): identity, mechanism, UPRmt reporter usage, triggers, regulation, phenotypes, aging links, recent 2023–2024 findings, and practical applications, with citations to the primary reviews and studies used.

9) Notes on gene symbol ambiguity and organism specificity
- The symbol hsp-60 can refer to mitochondrial HSP60 homologs in many species. Here, all claims were restricted to C. elegans hsp-60 or conserved HSP60/Cpn60 mechanisms, and the regulatory/phenotypic data were taken from C. elegans sources or cross‑validated reviews. The identity matches the UniProt P50140 annotation, organism is C. elegans, and domain/family annotations agree with the literature (haynes2022mitochondrialdysfunctionaging pages 5-6, fink1999chaperonemediatedproteinfolding. pages 6-7, minari2024newinsightsinto pages 3-4).

References (URLs and dates embedded above):
- Haynes & Hekimi, Genetics (2022-11-30): https://doi.org/10.1093/genetics/iyac160 (haynes2022mitochondrialdysfunctionaging pages 5-6)
- Kim et al., J Cell Biol (2024-02-26): https://doi.org/10.1083/jcb.202310005 (kim2024regulationofproteostasis pages 1-2)
- Chen et al., Aging Cell (2024-02-18): https://doi.org/10.1111/acel.14103 (jeong2017mitochondrialchaperonehsp‐60 pages 11-12)
- Jeong et al., EMBO J (2017-04-13): https://doi.org/10.15252/embj.201694781 (jeong2017mitochondrialchaperonehsp‐60 pages 3-5, jeong2017mitochondrialchaperonehsp‐60 pages 12-13, jeong2017mitochondrialchaperonehsp‐60 pages 11-12)
- Bennett et al., Nat Commun (2014-03-25): https://doi.org/10.1038/ncomms4483 (bennett2014activationofthe pages 6-6)
- Haeussler & Conradt, Methods Mol Biol (2022-01-01): https://doi.org/10.1007/978-1-0716-1732-8_16 (haeussler2022methodstostudy pages 16-18)
- Rauthan & Pilon, Worm (2015-10-14): https://doi.org/10.1080/21624054.2015.1096490 (rauthan2015achemicalscreen pages 1-3)
- Berry et al., microPublication Biology (2021-09-14): https://doi.org/10.17912/micropub.biology.000445 (berry2021decreasedmitochondrialmembrane pages 1-3)
- Runkel et al., PLoS Genet (2013-03-07): https://doi.org/10.1371/journal.pgen.1003346 (runkel2013surveillanceactivateddefensesblock pages 1-2)
- Liu et al., Sci Rep (2019-11-21): https://doi.org/10.1038/s41598-019-53004-9 (liu2019mitochondrialunfoldedprotein pages 1-2)
- Singh et al., Int J Mol Sci (2024-05-20): https://doi.org/10.3390/ijms25105483; Singh et al., IJMS (2024-04-15): https://doi.org/10.3390/ijms25084209 (singh2024molecularchaperoninhsp60 pages 1-2, singh2024heatshockresponse pages 12-13, singh2024heatshockresponse pages 13-15)
- Minari et al., BioChem (2024-04-01): https://doi.org/10.3390/biochem4020004 (minari2024newinsightsinto pages 3-4)
- Fink, Physiol Rev (1999-04-01): https://doi.org/10.1152/physrev.1999.79.2.425 (fink1999chaperonemediatedproteinfolding. pages 6-7, fink1999chaperonemediatedproteinfolding. pages 5-6)
- Kwon et al., BMB Rep (2018-06-30): https://doi.org/10.5483/bmbrep.2018.51.6.111 (kwon2018mitochondriamediateddefensemechanisms pages 2-3)

Conclusions
- C. elegans hsp-60 encodes a mitochondrial HSP60/Cpn60 chaperonin that executes ATP‑driven, HSP‑10–assisted protein folding in the mitochondrial matrix. In worms, hsp‑60 is a core UPRmt target and a widely used reporter readout. Mechanistically, ATFS‑1 is required for hsp‑60 induction, with HAF‑1/DVE‑1 contributing context‑dependently. Functionally, hsp‑60 not only ensures mitochondrial proteostasis but also contributes to innate immunity via p38/PMK‑1 signaling. Recent (2023–2024) studies refine UPRmt’s breadth (immunity, metabolism) and identify mitochondrial SAM as an upstream UPRmt trigger. Importantly, robust UPRmt activation (including hsp‑60 induction) is not a universal predictor of longevity and may be detrimental if chronic (haynes2022mitochondrialdysfunctionaging pages 5-6, kim2024regulationofproteostasis pages 1-2, jeong2017mitochondrialchaperonehsp‐60 pages 11-12, bennett2014activationofthe pages 6-6, jeong2017mitochondrialchaperonehsp‐60 pages 3-5).

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(jeong2017mitochondrialchaperonehsp‐60 pages 3-5): Dae‐Eun Jeong, Dongyeop Lee, Sun‐Young Hwang, Yujin Lee, Jee‐Eun Lee, Mihwa Seo, Wooseon Hwang, Keunhee Seo, Ara B Hwang, Murat Artan, Heehwa G Son, Jay‐Hyun Jo, Haeshim Baek, Young Min Oh, Youngjae Ryu, Hyung‐Jun Kim, Chang Man Ha, Joo‐Yeon Yoo, and Seung‐Jae V Lee. Mitochondrial chaperone hsp‐60 regulates anti‐bacterial immunity via p38 map kinase signaling. The EMBO Journal, 36:1046-1065, Apr 2017. URL: https://doi.org/10.15252/embj.201694781, doi:10.15252/embj.201694781. This article has 88 citations.
(kwon2018mitochondriamediateddefensemechanisms pages 2-3): Sujeong Kwon, Eun Ji E. Kim, and Seung-Jae V. Lee. Mitochondria-mediated defense mechanisms against pathogens in caenorhabditis elegans. BMB Reports, 51:274-279, Jun 2018. URL: https://doi.org/10.5483/bmbrep.2018.51.6.111, doi:10.5483/bmbrep.2018.51.6.111. This article has 29 citations and is from a peer-reviewed journal.
(singh2024heatshockresponse pages 12-13): Manish Kumar Singh, Yoonhwa Shin, Songhyun Ju, Sunhee Han, Wonchae Choe, Kyung-Sik Yoon, Sung Soo Kim, and Insug Kang. Heat shock response and heat shock proteins: current understanding and future opportunities in human diseases. International Journal of Molecular Sciences, 25:4209, Apr 2024. URL: https://doi.org/10.3390/ijms25084209, doi:10.3390/ijms25084209. This article has 133 citations and is from a poor quality or predatory journal.

Citations

kim2024regulationofproteostasis pages 1-2
haynes2022mitochondrialdysfunctionaging pages 5-6
bennett2014activationofthe pages 6-6
berry2021decreasedmitochondrialmembrane pages 1-3
liu2019mitochondrialunfoldedprotein pages 1-2
rauthan2015achemicalscreen pages 1-3
haeussler2022methodstostudy pages 16-18
minari2024newinsightsinto pages 3-4
runkel2013surveillanceactivateddefensesblock pages 1-2
kwon2018mitochondriamediateddefensemechanisms pages 2-3
singh2024heatshockresponse pages 13-15
kunachowicz2024heatshockproteins pages 10-11
singh2024heatshockresponse pages 12-13
https://doi.org/10.1083/jcb.202310005
https://doi.org/10.1111/acel.14103
https://doi.org/10.1093/genetics/iyac160
https://doi.org/10.15252/embj.201694781
https://doi.org/10.1038/ncomms4483
https://doi.org/10.17912/micropub.biology.000445
https://doi.org/10.1038/s41598-019-53004-9
https://doi.org/10.1080/21624054.2015.1096490
https://doi.org/10.3791/61001;
https://doi.org/10.3390/ijms25105483
https://doi.org/10.1152/physrev.1999.79.2.425
https://doi.org/10.3390/biochem4020004
https://doi.org/10.1007/978-1-0716-1732-8_16
https://doi.org/10.1371/journal.pgen.1003346
https://doi.org/10.5483/bmbrep.2018.51.6.111
https://doi.org/10.3390/ijms25105483;
https://doi.org/10.3390/ijms25084209
https://doi.org/10.1093/genetics/iyac160,
https://doi.org/10.1083/jcb.202310005,
https://doi.org/10.1152/physrev.1999.79.2.425,
https://doi.org/10.3390/biochem4020004,
https://doi.org/10.3390/ijms25105483,
https://doi.org/10.3390/ijms25084209,
https://doi.org/10.3390/cancers16081500,
https://doi.org/10.15252/embj.201694781,
https://doi.org/10.1007/978-1-0716-1732-8_16,
https://doi.org/10.1038/ncomms4483,
https://doi.org/10.1038/s41598-019-53004-9,
https://doi.org/10.17912/micropub.biology.000445,
https://doi.org/10.1371/journal.pgen.1003346,
https://doi.org/10.1080/21624054.2015.1096490,
https://doi.org/10.5483/bmbrep.2018.51.6.111,

📄 View Raw YAML

id: P50140
gene_symbol: hsp-60
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: HSP-60 is the C. elegans mitochondrial matrix chaperonin, a member 
  of the HSP60/GroEL family. It functions as an ATP-dependent protein folding 
  machine that works in concert with the co-chaperonin HSP-10 to assist folding 
  of newly imported mitochondrial proteins and to refold stress-damaged proteins
  in the mitochondrial matrix. HSP-60 assembles into double heptameric rings 
  (tetradecamer) forming a central folding chamber, and the ATP hydrolysis cycle
  drives conformational changes that encapsulate and fold substrate proteins. 
  The hsp-60 gene is a canonical target of the mitochondrial unfolded protein 
  response (UPRmt), regulated by the transcription factor ATFS-1. HSP-60::GFP 
  reporters are widely used as readouts of UPRmt activation. Beyond its 
  chaperone role, a cytosolic fraction of HSP-60 contributes to innate immunity 
  via stabilization of SEK-1 and activation of PMK-1/p38 MAPK signaling.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSP-60 is a bona fide protein folding chaperone. As a member of the
      GroEL/Cpn60 family, HSP-60 functions as an ATP-dependent protein folding 
      machine in the mitochondrial matrix, assisting newly imported proteins to 
      achieve their native conformation and refolding stress-damaged proteins 
      (Fink 1999, Singh 2024). The IBA annotation is phylogenetically 
      well-supported given the deep conservation of this function across all 
      domains of life.
    action: ACCEPT
    reason: Protein folding is the core molecular function of HSP-60. The 
      chaperonin mechanism is highly conserved from bacterial GroEL to 
      mitochondrial HSP60, and C. elegans HSP-60 contains all the canonical 
      Cpn60/GroEL domains required for this function. UniProt annotation 
      confirms this function.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: the mitochondrial matrix HSP70 and HSP60 chaperones, 
        encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were 
        selectively activated by perturbations that impair assembly of 
        multi-subunit mitochondrial complexes or by RNAi of genes encoding 
        mitochondrial chaperones or proteases, which lead to defective protein 
        folding and processing in the organelle
- term:
    id: GO:0008637
    label: apoptotic mitochondrial changes
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Human HSPD1/HSP60 has been implicated in apoptotic processes, 
      particularly mitochondrial changes during programmed cell death. However, 
      direct evidence for this role in C. elegans HSP-60 is limited. The 
      annotation is based on phylogenetic inference from mammalian studies.
    action: KEEP_AS_NON_CORE
    reason: While HSP60 family members have been linked to apoptosis in mammals 
      (e.g., cytoplasmic release during apoptosis), this represents a 
      secondary/downstream consequence rather than a core function of the C. 
      elegans chaperonin. The primary role of HSP-60 is protein folding in the 
      mitochondrial matrix. The annotation is phylogenetically inferred and 
      while not incorrect, represents a non-core function that may be 
      context-dependent.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSP-60 is primarily localized to the mitochondrial matrix, not the 
      inner membrane. Some association with the inner membrane may occur during 
      protein import assistance, but the functional localization is the matrix 
      compartment.
    action: MODIFY
    reason: The primary and well-established localization of HSP-60/Cpn60 family
      members is the mitochondrial matrix, where they perform their chaperone 
      function. UniProt annotates this as "Mitochondrion matrix." While 
      transient associations with the inner membrane may occur during substrate 
      protein import, the matrix is the canonical functional compartment. The 
      annotation GO:0005759 (mitochondrial matrix) is more accurate.
    proposed_replacement_terms:
    - id: GO:0005759
      label: mitochondrial matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The mitochondrial matrix is the canonical localization for HSP-60 
      where it performs its chaperone function. This is well-supported by the 
      UniProt record and extensive literature on Cpn60/GroEL family chaperonins 
      (Singh 2024, Fink 1999).
    action: ACCEPT
    reason: HSP-60 is nuclear-encoded, synthesized in the cytosol, and imported 
      into the mitochondrial matrix via an N-terminal targeting presequence, 
      where it folds imported matrix proteins and refolds stress-damaged 
      proteins. This is the correct and primary cellular component annotation.
    supported_by:
    - reference_id: file:worm/hsp-60/hsp-60-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion matrix.'
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSP-60 is a core effector and transcriptional target of the UPRmt. 
      The hsp-60 promoter is activated during mitochondrial stress as part of 
      the ATFS-1-dependent transcriptional program. HSP-60::GFP reporters are 
      canonical readouts of UPRmt activation (Haynes 2022, Yoneda 2004, 
      Benedetti 2006).
    action: ACCEPT
    reason: This is one of the core functions of HSP-60 in C. elegans. The 
      hsp-60 gene is a canonical UPRmt target, and hsp-60p::GFP reporters are 
      among the most widely used tools for monitoring UPRmt activation. HSP-60 
      protein functions as an effector that helps restore mitochondrial 
      proteostasis during stress.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: hsp-6 and hsp-60 induction was specific to perturbed 
        mitochondrial protein handling, as neither heat-shock nor endoplasmic 
        reticulum stress nor manipulations that impair mitochondrial steps in 
        intermediary metabolism or ATP synthesis activated the mitochondrial 
        chaperone genes. These observations support the existence of a 
        mitochondrial unfolded protein response
    - reference_id: PMID:16816413
      supporting_text: RNAi of ubl-5, a gene encoding a ubiquitin-like protein, 
        suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp 
        by the zc32 mutation and by other manipulations that promote 
        mitochondrial protein misfolding
- term:
    id: GO:0045041
    label: protein import into mitochondrial intermembrane space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSP-60 is implicated in assisting the folding of proteins imported 
      into mitochondria, but its primary role is in the matrix, not specifically
      the intermembrane space (IMS). The annotation may be too specific 
      regarding the compartment.
    action: MODIFY
    reason: HSP-60 assists protein folding in the mitochondrial matrix and can 
      assist newly imported proteins. However, proteins destined for the IMS use
      distinct import pathways (MIA/CHCHD4 pathway) and HSP-60 primarily 
      functions in the matrix. A more general term related to mitochondrial 
      protein import or matrix protein folding would be more accurate.
    proposed_replacement_terms:
    - id: GO:0006457
      label: protein folding
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSP-60 binds to its co-chaperonin HSP-10 (Cpn10/GroES family) to 
      form the functional chaperone complex. This interaction is essential for 
      the ATP-dependent protein folding cycle. The annotation reflects the 
      physical interaction between HSP-60 and HSP-10.
    action: ACCEPT
    reason: The HSP-60/HSP-10 interaction is a fundamental aspect of chaperonin 
      function. HSP-10 (Cpn10) is a heptameric lid that binds to the apical 
      domains of HSP-60 to cap the folding chamber. This is well-established 
      from structural and biochemical studies of the GroEL/GroES system and 
      conserved in mitochondrial chaperonins.
    supported_by:
    - reference_id: file:worm/hsp-60/hsp-60-deep-research-falcon.md
      supporting_text: HSP-60/Cpn60 forms a double-ring (two heptameric rings) 
        folding cage that captures non-native substrates; HSP-10 (Cpn10/GroES) 
        caps the cavity and an ATP-binding/hydrolysis cycle drives 
        conformational changes to permit folding and release
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: HSP-60 binds ATP as part of its chaperone cycle. The annotation is 
      correct but overly general - ATP binding (GO:0005524) is a more specific 
      and informative annotation.
    action: ACCEPT
    reason: While correct, this annotation is subsumed by the more specific ATP 
      binding annotation. HSP-60 contains the conserved ATP-binding equatorial 
      domain of Cpn60/GroEL chaperonins. The annotation can be retained as it is
      not incorrect, though ATP binding is more informative.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: HSP-60 binds ATP in its equatorial domain, and ATP hydrolysis 
      drives the conformational changes necessary for protein folding. This is a
      core molecular function of all Cpn60/GroEL family chaperonins.
    action: ACCEPT
    reason: ATP binding and hydrolysis are essential for HSP-60 function. The 
      ATP-driven conformational cycle is fundamental to chaperonin-assisted 
      protein folding. UniProt lists ATP-binding as a keyword for this protein.
    supported_by:
    - reference_id: file:worm/hsp-60/hsp-60-uniprot.txt
      supporting_text: KW   ATP-binding; Chaperone; Mitochondrion; 
        Nucleotide-binding
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Duplicate annotation with IBA evidence above. The mitochondrial 
      matrix localization is well-supported and correct.
    action: ACCEPT
    reason: Consistent with IBA annotation and UniProt record. Multiple evidence
      sources converging on the same correct annotation strengthens confidence.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate annotation with IBA evidence above. Protein folding is 
      the core function of HSP-60. The InterPro-based annotation supports the 
      phylogenetic inference.
    action: ACCEPT
    reason: Consistent with IBA annotation. The convergence of phylogenetic and 
      domain-based evidence strengthens the annotation.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: HSP-60 assists in refolding stress-damaged proteins in the 
      mitochondrial matrix. This is consistent with its role as a chaperonin and
      its induction during mitochondrial stress.
    action: ACCEPT
    reason: Protein refolding under stress conditions is a well-established 
      function of HSP60 family chaperonins. UniProt states HSP-60 "may also 
      prevent misfolding and promote the refolding and proper assembly of 
      unfolded polypeptides generated under stress conditions in the 
      mitochondrial matrix."
    supported_by:
    - reference_id: file:worm/hsp-60/hsp-60-uniprot.txt
      supporting_text: May also prevent misfolding and promote the refolding and
        proper assembly of unfolded polypeptides generated under stress 
        conditions in the mitochondrial matrix
- term:
    id: GO:0140662
    label: ATP-dependent protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This molecular function annotation accurately captures the core 
      enzymatic/chaperone activity of HSP-60 - ATP-dependent protein folding.
    action: ACCEPT
    reason: This is an accurate and informative molecular function annotation 
      for HSP-60. The chaperonin uses ATP binding and hydrolysis to drive 
      conformational changes that facilitate protein folding in the chamber 
      formed between the two heptameric rings.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:17189267
  review:
    summary: Kimura et al. (2007) studied HSP-6 (mtHsp70) knockdown effects and 
      showed that HSP-60 levels are reduced along with other mitochondrial 
      proteins, demonstrating HSP-60's mitochondrial localization. This provides
      experimental support for mitochondrial localization.
    action: ACCEPT
    reason: The IDA evidence from PMID:17189267 supports mitochondrial 
      localization. While the more specific term "mitochondrial matrix" is also 
      annotated, the general mitochondrion term is not incorrect and represents 
      valid experimental evidence.
    supported_by:
    - reference_id: PMID:17189267
      supporting_text: Knockdown of HSP-6 by RNA interference in young adult 
        nematodes caused a reduction in the levels of ATP-2, HSP-60 and CLK-1, 
        leading to abnormal mitochondrial morphology
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:17925224
  review:
    summary: Haynes et al. (2007) showed that DVE-1, a homeodomain transcription
      factor, binds to the hsp-60 promoter during UPRmt activation. This 
      annotation appears to suggest HSP-60 protein interacts with transcription 
      factors, which is not the main finding. The study describes 
      transcriptional regulation OF hsp-60, not by HSP-60.
    action: REMOVE
    reason: This annotation appears to be an error or misinterpretation. 
      PMID:17925224 describes the DVE-1 transcription factor binding to the 
      hsp-60 PROMOTER to regulate its expression during UPRmt, not HSP-60 
      protein binding to transcription factors. The hsp-60 gene is a 
      transcriptional TARGET of DVE-1, not a protein interactor. The IPI 
      evidence code suggests protein-protein interaction, but the paper 
      describes transcriptional regulation of the hsp-60 gene.
    supported_by:
    - reference_id: PMID:17925224
      supporting_text: Activation of the UPR(mt) correlates temporally and 
        spatially with nuclear redistribution of DVE-1 and with its enhanced 
        binding to the promoters of mitochondrial chaperone genes
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IEP
  original_reference_id: PMID:15280428
  review:
    summary: Yoneda et al. (2004) showed hsp-60 gene expression is induced 
      during UPRmt. This IEP (Inferred from Expression Pattern) annotation is 
      appropriate as hsp-60 expression correlates with UPRmt activation.
    action: ACCEPT
    reason: The IEP evidence is valid - hsp-60 expression is upregulated during 
      mitochondrial stress as part of the UPRmt transcriptional program. This is
      a landmark paper establishing the UPRmt in C. elegans.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: the mitochondrial matrix HSP70 and HSP60 chaperones, 
        encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were 
        selectively activated by perturbations that impair assembly of 
        multi-subunit mitochondrial complexes
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:15280428
  review:
    summary: The IMP (Inferred from Mutant Phenotype) annotation suggests 
      functional involvement in UPRmt was demonstrated through genetic 
      manipulation. Yoneda et al. (2004) showed that RNAi of mitochondrial 
      chaperones/proteases activates hsp-60 expression.
    action: ACCEPT
    reason: HSP-60 is both a transcriptional target and functional effector of 
      the UPRmt. The protein helps restore proteostasis in the mitochondrial 
      matrix during stress. Multiple evidence types (IBA, IEP, IMP) converge on 
      this annotation.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: RNAi of genes encoding mitochondrial chaperones or 
        proteases, which lead to defective protein folding and processing in the
        organelle [activate hsp-60/hsp-6]
      full_text_unavailable: true
- term:
    id: GO:0002119
    label: nematode larval development
  evidence_type: IMP
  original_reference_id: PMID:15280428
  review:
    summary: Yoneda et al. (2004) demonstrated that perturbing mitochondrial 
      proteostasis affects development, and hsp-60 is involved in the response. 
      This represents a downstream phenotypic consequence rather than a specific
      molecular function.
    action: KEEP_AS_NON_CORE
    reason: While HSP-60 is essential for proper development (as are many 
      mitochondrial proteins), larval development is a broad phenotypic readout 
      rather than a specific molecular function. The annotation reflects 
      pleiotropy - loss of mitochondrial chaperone function affects many 
      processes including development. This is a valid but non-core annotation.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: Jul 27. Compartment-specific perturbation of protein 
        handling activates genes encoding mitochondrial chaperones.
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:16816413
  review:
    summary: Benedetti et al. (2006) showed that perturbation of UPRmt signaling
      (via ubl-5 RNAi) affects mitochondrial morphology and assembly of 
      mitochondrial complexes. HSP-60, as an effector chaperone, contributes to 
      proper mitochondrial organization.
    action: ACCEPT
    reason: HSP-60 contributes to proper folding and assembly of mitochondrial 
      protein complexes, which is essential for mitochondrial organization. The 
      study shows that compromising UPRmt (and thus chaperone function) leads to
      abnormal mitochondrial morphology.
    supported_by:
    - reference_id: PMID:16816413
      supporting_text: Mitochondrial morphology and assembly of multi-subunit 
        mitochondrial complexes of biotinylated proteins are also perturbed in 
        ubl-5(RNAi) worms, indicating that UBL-5 also counteracts physiological 
        levels of mitochondrial stress
- term:
    id: GO:0009792
    label: embryo development ending in birth or egg hatching
  evidence_type: IMP
  original_reference_id: PMID:15280428
  review:
    summary: Similar to larval development, this annotation reflects that HSP-60
      function is required for normal embryonic development. This is a broad 
      phenotypic consequence of mitochondrial chaperone function.
    action: KEEP_AS_NON_CORE
    reason: Embryonic development is a broad biological process affected by 
      mitochondrial dysfunction. While the annotation is valid, it represents 
      pleiotropy rather than a specific molecular role. Essential mitochondrial 
      proteins affect many developmental processes.
    supported_by:
    - reference_id: PMID:15280428
      supporting_text: Jul 27. Compartment-specific perturbation of protein 
        handling activates genes encoding mitochondrial chaperones.
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: TAS
  original_reference_id: PMID:15280428
  review:
    summary: Jeong et al. (2017, EMBO J) demonstrated that HSP-60 contributes to
      antibacterial immunity via the p38 MAPK/PMK-1 pathway. A cytosolic 
      fraction of HSP-60 stabilizes SEK-1 and promotes PMK-1 phosphorylation, 
      enhancing resistance to P. aeruginosa. This function is described in the 
      deep research but the primary paper PMID is not yet in the publications 
      cache.
    action: NEW
    reason: This represents a significant non-canonical function of HSP-60 
      supported by direct experimental evidence. The deep research document 
      cites Jeong et al. (2017, EMBO J, doi:10.15252/embj.201694781) showing 
      hsp-60 RNAi reduces PMK-1 activity and pathogen resistance, while 
      cytosolic HSP-60 overexpression improves PA14 resistance.
    supported_by:
    - reference_id: file:worm/hsp-60/hsp-60-deep-research-falcon.md
      supporting_text: hsp-60 RNAi lowers PMK-1 activity (decreased PMK-1 
        reporters and phospho-PMK-1) and reduces survival on PA14; cytosolic 
        HSP-60 overexpression improves PA14 resistance, consistent with HSP-60 
        acting via p38/PMK-1
    - reference_id: PMID:15280428
      supporting_text: Jul 27. Compartment-specific perturbation of protein 
        handling activates genes encoding mitochondrial chaperones.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings:
  - statement: Domain-based evidence supporting ATP-dependent chaperone function
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: Phylogenetic inference from conserved HSP60/GroEL family function
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: Nucleotide binding from UniProt keywords
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings:
  - statement: Mitochondrial matrix localization from UniProt
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: ATP binding evidence from combined computational methods
- id: PMID:15280428
  title: Compartment-specific perturbation of protein handling activates genes 
    encoding mitochondrial chaperones.
  findings:
  - statement: Landmark paper establishing the UPRmt in C. elegans
    supporting_text: We found that the mitochondrial matrix HSP70 and HSP60 
      chaperones, encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, 
      were selectively activated by perturbations that impair assembly of 
      multi-subunit mitochondrial complexes
  - statement: hsp-60 and hsp-6 are selectively induced by mitochondrial protein
      folding stress
    supporting_text: hsp-6 and hsp-60 induction was specific to perturbed 
      mitochondrial protein handling
  - statement: UPRmt is distinct from heat shock and ER stress responses
    supporting_text: neither heat-shock nor endoplasmic reticulum stress nor 
      manipulations that impair mitochondrial steps in intermediary metabolism 
      or ATP synthesis activated the mitochondrial chaperone genes
- id: PMID:16816413
  title: Ubiquitin-like protein 5 positively regulates chaperone gene expression
    in the mitochondrial unfolded protein response.
  findings:
  - statement: UBL-5 is required for UPRmt signaling
    supporting_text: RNAi of ubl-5, a gene encoding a ubiquitin-like protein, 
      suppresses activation of the UPR(mt) markers hsp-60::gfp and hsp-6::gfp
  - statement: hsp-60::GFP is a canonical UPRmt reporter
    supporting_text: suppresses activation of the UPR(mt) markers hsp-60::gfp 
      and hsp-6::gfp by the zc32 mutation and by other manipulations that 
      promote mitochondrial protein misfolding
  - statement: UPRmt perturbation affects mitochondrial morphology
    supporting_text: Mitochondrial morphology and assembly of multi-subunit 
      mitochondrial complexes of biotinylated proteins are also perturbed in 
      ubl-5(RNAi) worms
- id: PMID:17189267
  title: Knockdown of mitochondrial heat shock protein 70 promotes progeria-like
    phenotypes in caenorhabditis elegans.
  findings:
  - statement: HSP-6 knockdown reduces HSP-60 levels
    supporting_text: Knockdown of HSP-6 by RNA interference in young adult 
      nematodes caused a reduction in the levels of ATP-2, HSP-60 and CLK-1
  - statement: Demonstrates interdependence of mitochondrial chaperones
    supporting_text: Mitochondrial HSP-60 and ATP-2 were also reduced following 
      the reduction of HSP-6 during aging
  - statement: Provides IDA evidence for mitochondrial localization
    supporting_text: leading to abnormal mitochondrial morphology and lower ATP 
      levels
- id: PMID:17925224
  title: ClpP mediates activation of a mitochondrial unfolded protein response 
    in C. elegans.
  findings:
  - statement: DVE-1 and UBL-5 form complex during UPRmt
    supporting_text: Unfolded protein stress in the mitochondria correlates with
      complex formation between a homeodomain-containing transcription factor 
      DVE-1 and the small ubiquitin-like protein UBL-5
  - statement: DVE-1 binds promoters of mitochondrial chaperone genes including 
      hsp-60
    supporting_text: Activation of the UPR(mt) correlates temporally and 
      spatially with nuclear redistribution of DVE-1 and with its enhanced 
      binding to the promoters of mitochondrial chaperone genes
  - statement: ClpP is required for UPRmt signaling
    supporting_text: These events and the downstream UPR(mt) are attenuated in 
      animals with reduced activity of clpp-1, which encodes a mitochondrial 
      matrix protease homologous to bacterial ClpP
core_functions:
- molecular_function:
    id: GO:0140662
    label: ATP-dependent protein folding chaperone
  description: Core molecular function - HSP-60 is a GroEL/Cpn60 family 
    chaperonin that uses ATP binding and hydrolysis to drive protein folding in 
    a chamber formed by double heptameric rings with HSP-10 co-chaperonin lid.
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  directly_involved_in:
  - id: GO:0034514
    label: mitochondrial unfolded protein response
proposed_new_terms: []
suggested_questions:
- question: What is the substrate specificity of C. elegans HSP-60? Are there 
    specific mitochondrial proteins that preferentially require HSP-60 for 
    folding?
- question: How does the cytosolic fraction of HSP-60 contribute to innate 
    immunity? Is this a regulated process or does it occur constitutively?
- question: Does HSP-60 have roles in mitochondrial protein import beyond 
    folding newly imported proteins?
suggested_experiments:
- description: Identify HSP-60 client proteins using proximity labeling 
    (BioID/TurboID) in the mitochondrial matrix under normal and stress 
    conditions.
  hypothesis: HSP-60 has specific client proteins in the mitochondrial matrix 
    that require chaperonin assistance for folding.
- description: Characterize the cytosolic HSP-60 pool using subcellular 
    fractionation and determine what regulates its distribution between 
    mitochondria and cytosol.
  hypothesis: The cytosolic fraction of HSP-60 is regulated and contributes to 
    innate immunity signaling under specific conditions.
- description: Test whether HSP-60 co-localizes with the TIM/TOM import 
    machinery using super-resolution microscopy.
  hypothesis: HSP-60 interacts with the mitochondrial import machinery to assist
    folding of newly imported proteins.
tags:
- caeel-upr-stress

hsp-60

Gene Description

Existing Annotations Review

Core Functions

Core molecular function - HSP-60 is a GroEL/Cpn60 family chaperonin that uses ATP binding and hydrolysis to drive protein folding in a chamber formed by double heptameric rings with HSP-10 co-chaperonin lid.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

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Question

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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