Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation from phylogenetic inference. While mammalian BiP/GRP78 has been reported in nuclear compartments under certain stress conditions, HSP-4 in C. elegans is primarily characterized as an ER lumen chaperone. The UniProt record and deep research consistently describe HSP-4 as ER-localized. Nuclear localization may reflect conservation of potential regulatory functions but is not a primary localization in C. elegans. Reason: While phylogenetically conserved from mammalian BiP, nuclear localization is not a well-documented aspect of HSP-4 function in C. elegans. The protein contains an ER retention signal (HDEL) and is primarily ER-localized according to UniProt and functional studies. This annotation may represent an ancestral or minor localization pattern. Supporting Evidence: UniProt:P20163 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation from phylogenetic inference. HSP-4 is primarily ER-localized with an ER retention signal. Some cytoplasmic localization may occur during synthesis or under stress conditions, but the primary functional location is the ER lumen. Reason: This annotation likely reflects the biosynthetic pathway or minor localization patterns conserved in the HSP70 family. The primary functional location of HSP-4 is the ER lumen, as supported by the HDEL retention signal and functional studies. Supporting Evidence: UniProt:P20163 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: HSP-4/BiP is an ATPase that uses ATP hydrolysis to drive its chaperone cycle. UniProt assigns EC 3.6.4.10 (ATP-dependent chaperone activity). The deep research confirms that HSP-4 operates through an ATPase-driven chaperone cycle that binds and releases unfolded client polypeptides in the ER lumen. Reason: ATP hydrolysis is a core molecular function of HSP70 family members including BiP/HSP-4. This activity is essential for the chaperone cycle. UniProt provides catalytic activity annotation with the reaction: ATP + H2O = ADP + phosphate + H(+). Supporting Evidence: UniProt:P20163 Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, file:worm/hsp-4/hsp-4-deep-research-falcon.md HSP-4, as a BiP ortholog, operates through an ATPase-driven chaperone cycle that binds and releases unfolded client polypeptides in the ER lumen
GO:0031072 heat shock protein binding	IBA GO_REF:0000033	ACCEPT	Summary: HSP70 family members interact with co-chaperones including J domain-containing proteins (DnaJ/Hsp40) and nucleotide exchange factors. HSP-4/BiP requires co-chaperones for efficient substrate recognition and ATPase regulation. Reason: This is a well-established function for HSP70/BiP family members. UniProt notes that J domain-containing co-chaperones stimulate the ATPase activity and are required for efficient substrate recognition. This interaction is central to the chaperone mechanism. Supporting Evidence: UniProt:P20163 J domain-containing co-chaperones stimulate the ATPase activity and are required for efficient substrate recognition
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	ACCEPT	Summary: HSP-4/BiP is an ER-resident molecular chaperone central to ER proteostasis. It assists protein folding and quality control in the ER lumen. The deep research confirms HSP-4 participates in ATP-dependent binding/release of unfolded or nascent client polypeptides. Reason: This is the core molecular function of HSP-4/BiP. It plays a key role in protein folding and quality control in the ER lumen. Overexpression of HSP-4 rescues dendrite morphogenesis defects in ire-1 mutants by restoring protein folding capacity (PMID:26052671). Supporting Evidence: UniProt:P20163 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen PMID:26052671 overexpression of hsp-4 in PVD restored normal dendritic branches in ire-1 mutants
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: BiP/HSP-4 is involved in ER-associated degradation (ERAD) by recognizing misfolded proteins in the ER. The deep research notes HSP-4 involvement in ERAD-related processes and interaction with ERAD components. Reason: BiP/HSP-4 functions in ERAD by recognizing and retaining misfolded proteins for degradation. PMID:12186849 demonstrates genetic interaction between hsp-4 and ERAD component sel-1, and shows that RNAi of sel-1 activates the hsp-4::gfp ER stress reporter in an xbp-1-dependent manner. Supporting Evidence: PMID:12186849 RNAi of sel-1, the C. elegans homologue of the yeast ERAD gene HRD3
GO:0016020 membrane	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: HSP-4 is a soluble ER lumen protein, not a membrane protein. It may associate with ER membrane peripherally through interactions with membrane-bound clients or ERAD components, but is not an integral membrane protein. Reason: This term is overly broad and imprecise. HSP-4/BiP is a soluble protein in the ER lumen with a HDEL retention signal. While it may interact with membrane-associated substrates, it is not itself a membrane protein. The more specific terms GO:0005788 (ER lumen) and GO:0034663 (ER chaperone complex) are more appropriate. Proposed replacements: endoplasmic reticulum lumen
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: HSP70/BiP chaperones assist in protein refolding as part of their quality control function. This is a well-established activity for the HSP70 family. Reason: Protein refolding is a core function of HSP70 family chaperones including BiP/HSP-4. The ATP-driven chaperone cycle allows iterative binding and release of substrates to promote proper folding. Supporting Evidence: UniProt:P20163 The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate- binding (SBD) domains
GO:0034663 endoplasmic reticulum chaperone complex	IBA GO_REF:0000033	ACCEPT	Summary: HSP-4/BiP functions within ER chaperone complexes with co-chaperones and other quality control machinery. This is supported by both phylogenetic inference and ISS evidence from PMID:11779465. Reason: HSP-4 is a core component of the ER chaperone machinery, functioning with co-chaperones and other quality control proteins. This localization is well-supported by the protein's known function. Supporting Evidence: UniProt:P20163 J domain-containing co-chaperones stimulate the ATPase activity and are required for efficient substrate recognition
GO:0005788 endoplasmic reticulum lumen	IBA GO_REF:0000033	ACCEPT	Summary: HSP-4 is localized to the ER lumen. This is the primary functional location of BiP/GRP78 homologs. The protein contains a signal peptide and HDEL ER retention motif. Reason: This is the primary and well-established localization of HSP-4/BiP. UniProt clearly states ER lumen localization. The protein has a signal peptide (aa 1-17) and HDEL ER retention motif (aa 654-657). Supporting Evidence: UniProt:P20163 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen PMID:26052671 we first examined the subcellular localization of HSP-4 and found that HSP-4::GFP was exclusively localized in the PVD soma
GO:0030968 endoplasmic reticulum unfolded protein response	IBA GO_REF:0000033	ACCEPT	Summary: HSP-4/BiP is a classical UPR target gene and effector. Its expression is strongly induced during ER stress, and the hsp-4::GFP reporter is the standard UPR marker in C. elegans. HSP-4 also regulates UPR signaling through interaction with IRE-1. Reason: HSP-4 is both a target and effector of the ER UPR. It is transcriptionally induced by the IRE-1/XBP-1 pathway during ER stress. Multiple publications establish hsp-4 as a core UPR marker and functional component. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress PMID:12186849 the signaling pathway initiated by IRE1 exerts nearly complete control over the induction of well-characterized components of ER client protein processing machinery, such as BiP (hsp-4)
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. HSP-4 binds ATP as part of its chaperone cycle. This is a parent term of ATP binding. Reason: This is a correct but general annotation. HSP-4 has well-characterized ATP binding and hydrolysis activities. UniProt provides detailed ATP binding site information (residues 38-41, 99, 229-231, 295-302, 366-369). Supporting Evidence: UniProt:P20163 GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from automated methods. HSP-4 contains a well-characterized ATP binding domain. ATP binding is essential for the chaperone cycle. Reason: ATP binding is a core molecular function of HSP-4/BiP. UniProt provides detailed annotation of ATP binding sites and the protein has crystal structure data for the peptide-binding domain (PDB:2OP6). Supporting Evidence: UniProt:P20163 GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location mapping. This duplicates the IBA annotation but from a different source. Both are correct. Reason: ER lumen localization is well-established for HSP-4/BiP. Multiple evidence types supporting the same annotation is appropriate. Supporting Evidence: UniProt:P20163 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from keyword mapping. HSP-4 has ATPase activity (hydrolyzes ATP). This is a parent term of ATP hydrolysis activity. Reason: This is a correct but general annotation. HSP-4 is an ATPase with hydrolase activity. The more specific term GO:0016887 (ATP hydrolysis activity) is also annotated. Supporting Evidence: UniProt:P20163 EC=3.6.4.10 {ECO:0000250\|UniProtKB:P11021}
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from automated methods. This duplicates the IBA annotation for ATP hydrolysis activity. Both are correct. Reason: ATP hydrolysis is a core molecular function of HSP-4/BiP, essential for the chaperone cycle. Multiple evidence types are appropriate. Supporting Evidence: UniProt:P20163 Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065,
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning. This duplicates other annotations for UPR involvement. HSP-4 is a well-established UPR component. Reason: HSP-4 involvement in the ER UPR is well-established. Multiple evidence sources supporting this annotation is appropriate. Supporting Evidence: PMID:12186849 BiP (hsp-4), protein disulfide isomerases, and 4-prolyl hydroxylases
GO:0030968 endoplasmic reticulum unfolded protein response	IEP PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: IEP annotation based on expression pattern. Shen et al. (2001) established that hsp-4 is a UPR target gene regulated by ire-1/xbp-1 signaling in C. elegans. Reason: PMID:11779465 is a foundational paper establishing the UPR pathway in C. elegans. It demonstrates that ire-1-mediated splicing of xbp-1 is required for UPR gene transcription including hsp-4. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress
GO:0030968 endoplasmic reticulum unfolded protein response	IEP PMID:11780124 IRE1 couples endoplasmic reticulum load to secretory capacit...	ACCEPT	Summary: IEP annotation based on expression pattern. Calfon et al. (2002) demonstrated that xbp-1 processing by IRE1 is conserved in C. elegans and activates UPR target genes. Reason: PMID:11780124 demonstrates that IRE1-mediated XBP-1 mRNA splicing activates UPR target genes in C. elegans, establishing the conserved IRE1/XBP-1 pathway. Supporting Evidence: PMID:11780124 mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans
GO:0030968 endoplasmic reticulum unfolded protein response	IEP PMID:18216284 APY-1, a novel Caenorhabditis elegans apyrase involved in un...	ACCEPT	Summary: IEP annotation based on expression pattern. Uccelletti et al. (2008) showed that ER stress induced by tunicamycin or high temperature results in increased hsp-4 transcription, dependent on both ire-1 and atf-6. Reason: PMID:18216284 demonstrates that hsp-4 induction during ER stress requires both IRE-1 and ATF-6 sensors, showing branch redundancy in UPR regulation. Supporting Evidence: PMID:18216284 ER stress induced by tunicamycin or high temperature resulted in increased transcription of apy-1. This increase was not observed in C. elegans mutants defective in ire-1 or atf-6
GO:0030968 endoplasmic reticulum unfolded protein response	HEP PMID:12186849 A survival pathway for Caenorhabditis elegans with a blocked...	ACCEPT	Summary: HEP annotation based on expression pattern from high-throughput experiment. Urano et al. (2002) used microarray analysis to characterize UPR target genes and showed hsp-4 induction is xbp-1-dependent. Reason: PMID:12186849 provides genome-wide evidence that hsp-4 is a robustly induced UPR target gene dependent on xbp-1. The study used cDNA microarrays and showed hsp-4 induction in wild-type but not xbp-1 mutants. Supporting Evidence: PMID:12186849 the signaling pathway initiated by IRE1 exerts nearly complete control over the induction of well-characterized components of ER client protein processing machinery, such as BiP (hsp-4)
GO:0005791 rough endoplasmic reticulum	IDA PMID:26052671 The unfolded protein response is required for dendrite morph...	ACCEPT	Summary: IDA annotation based on direct assay. Wei et al. (2015) showed that HSP-4::GFP co-localized with the rough ER marker TRAM in PVD neurons, demonstrating localization to the rough ER. Reason: PMID:26052671 provides direct imaging evidence that HSP-4 co-localizes with the rough ER marker TRAM, consistent with BiP's known function in nascent protein folding. Supporting Evidence: PMID:26052671 we first examined the subcellular localization of HSP-4 and found that HSP-4::GFP was exclusively localized in the PVD soma
GO:0030968 endoplasmic reticulum unfolded protein response	IEP PMID:15280428 Compartment-specific perturbation of protein handling activa...	ACCEPT	Summary: IEP annotation based on expression pattern. Yoneda et al. (2004) demonstrated compartment-specific stress responses and showed hsp-4 induction is specific to ER stress, not mitochondrial stress. Reason: PMID:15280428 establishes the specificity of hsp-4 induction to ER stress, distinguishing it from mitochondrial UPR. This supports HSP-4's specific role in ER proteostasis. 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
GO:0034663 endoplasmic reticulum chaperone complex	ISS PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: ISS annotation based on sequence similarity. HSP-4 functions in ER chaperone complexes similar to mammalian BiP. Reason: HSP-4 is orthologous to mammalian BiP, which functions in ER chaperone complexes. The functional conservation is supported by rescue experiments and pathway conservation. Supporting Evidence: UniProt:P20163 Belongs to the heat shock protein 70 family PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:24068940 Integration of the unfolded protein and oxidative stress res...	UNDECIDED	Summary: IPI annotation based on physical interaction. Glover-Cutter et al. (2013) showed that SKN-1/Nrf transcription factor regulates hsp-4 during ER stress. This annotation may reflect interaction data from ChIP or co-IP experiments. Reason: This annotation suggests HSP-4 physically interacts with transcription factors. While SKN-1 regulates hsp-4 transcription, HSP-4 is an ER lumen protein and direct binding to transcription factors would be unexpected. The annotation may reflect a database error or indirect interaction. Further review of the original paper is needed to verify the specific interaction claimed. Supporting Evidence: PMID:24068940 Sep 12. Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf.
GO:0006457 protein folding	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations.

Core Functions

HSP-4/BiP is the major ER-resident HSP70 chaperone that assists protein folding in the ER lumen. It uses ATP-dependent cycles of binding and release to promote proper folding of nascent and unfolded proteins. This is the primary molecular function of HSP-4.

Molecular Function:

protein folding chaperone

Directly Involved In:

endoplasmic reticulum unfolded protein response ERAD pathway

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

UniProt:P20163
Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen
PMID:26052671
overexpression of hsp-4 in PVD restored normal dendritic branches in ire-1 mutants

ATP hydrolysis drives the HSP-4 chaperone cycle. Allosteric coupling between the nucleotide-binding and substrate-binding domains allows regulated binding and release of client proteins.

Molecular Function:

ATP hydrolysis activity

Directly Involved In:

protein folding

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

UniProt:P20163
Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065,

HSP-4 binds ATP as part of its chaperone mechanism, using allosteric regulation between nucleotide-binding and substrate-binding domains to control substrate binding affinity.

Molecular Function:

ATP binding

Directly Involved In:

protein folding

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

UniProt:P20163
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

IBA annotations from PANTHER phylogenetic trees provide evolutionary evidence for HSP-4 function

GO_REF:0000043

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

UniProt keyword mappings provide IEA annotations

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

UniProt subcellular location provides localization annotations

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

Machine learning predictions support UPR involvement

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Combined evidence supports ATP binding and hydrolysis functions

PMID:11779465

Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development.

Established that C. elegans requires ire-1-mediated splicing of xbp-1 for UPR gene transcription

"C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress"
Demonstrated that ire-1/xbp-1 and pek-1 act in complementary pathways essential for development

"ire-1/xbp-1 acts with pek-1, a protein kinase that mediates translation attenuation, in complementary pathways that are essential for worm development and survival"
hsp-4 identified as a UPR target gene

"C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress"

PMID:11780124

IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.

Demonstrated conserved IRE1-dependent XBP-1 mRNA splicing in C. elegans
Established XBP-1 as a key UPR transcription factor

PMID:12186849

A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.

Genome-wide survey showing hsp-4 (BiP) is robustly induced during UPR in xbp-1-dependent manner
Established hsp-4::gfp as a standard ER stress reporter
Demonstrated genetic interactions between UPR components and ERAD genes

PMID:15280428

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

Demonstrated that hsp-4 induction is specific to ER stress, not mitochondrial stress
Established compartment-specific UPR signaling

PMID:18216284

APY-1, a novel Caenorhabditis elegans apyrase involved in unfolded protein response signalling and stress responses.

Showed that ER stress by tunicamycin or heat induces hsp-4 transcription
Demonstrated requirement of both ire-1 and atf-6 for full UPR induction

PMID:24068940

Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf.

Showed SKN-1/Nrf regulates transcription of UPR genes including hsp-4
Demonstrated integration of oxidative and ER stress responses

PMID:26052671

The unfolded protein response is required for dendrite morphogenesis.

Demonstrated HSP-4::GFP co-localizes with rough ER marker TRAM
Showed that HSP-4 overexpression rescues dendritic defects in ire-1 mutants
Established HSP-4's role in protein folding capacity for dendrite development

urban2025functionallydiversifiedcaenorhabditis

Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy

Demonstrated functional diversification between HSP-3 and HSP-4
HSP-4 specialized for interorganellar signaling and ER-stress mitigation
HSP-4 regulates ER-phagy via Sec-62 (C18E9.2) and crosstalk with IRE-1

waldherr2024endoplasmicreticulumunfolded

Endoplasmic reticulum unfolded protein response transcriptional targets of xbp-1s mediate rescue from tauopathy

hsp-4 identified among 116 XBP-1s upregulated genes
HSP-4 upregulation partially rescues tauopathy
ATF-6 required alongside IRE-1/XBP-1 for full neuroprotection

xu2024theunfoldedprotein

The unfolded protein response of the endoplasmic reticulum protects Caenorhabditis elegans against DNA damage caused by stalled replication forks

DNA primase depletion induces germline hsp-4 expression
hsp-4 induction can be ATF-6 dependent and partly IRE-1/XBP-1 independent
Demonstrated context-dependent UPR branch requirements

Suggested Experiments

Experiment: Proximity labeling (BioID/TurboID) to identify HSP-4 client proteins and interaction partners in vivo under basal and stress conditions.

Hypothesis: HSP-4 has specific client proteins distinct from HSP-3

Type: proteomics

Experiment: Comparative proteomics of hsp-4 vs hsp-3 mutants to identify specific clients and pathway dependencies of each paralog.

Hypothesis: HSP-3 and HSP-4 have distinct client protein profiles

Type: comparative proteomics

Experiment: Live imaging of endogenous HSP-4 reporters under various stress conditions to understand tissue-specific and temporal dynamics of expression.

Hypothesis: HSP-4 expression shows tissue-specific patterns during stress

Type: live imaging

📚 Additional Documentation

Deep Research Falcon

(hsp-4-deep-research-falcon.md)

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gene_id: hsp-4
gene_symbol: hsp-4
uniprot_accession: P20163
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Flags: Precursor;'
gene_info: Name=hsp-4; Synonyms=hsp70d; ORFNames=F43E2.8;
organism_full: Caenorhabditis elegans.
protein_family: Belongs to the heat shock protein 70 family. .
protein_domains: ATPase_NBD. (IPR043129); BIP_NBD. (IPR042050); Heat_shock_70_CS.
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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: P20163
Protein Description: RecName: Full=Endoplasmic reticulum chaperone BiP homolog {ECO:0000305}; AltName: Full=Heat shock 70 kDa protein D; EC=3.6.4.10 {ECO:0000250|UniProtKB:P11021}; Flags: Precursor;
Gene Information: Name=hsp-4; Synonyms=hsp70d; ORFNames=F43E2.8;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the heat shock protein 70 family. .
Key Domains: ATPase_NBD. (IPR043129); BIP_NBD. (IPR042050); Heat_shock_70_CS. (IPR018181); HSP70_C_sf. (IPR029048); HSP70_peptide-bd_sf. (IPR029047)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-4" 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-4' 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-4 (gene ID: hsp-4, UniProt: P20163) 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: P20163
Protein Description: RecName: Full=Endoplasmic reticulum chaperone BiP homolog {ECO:0000305}; AltName: Full=Heat shock 70 kDa protein D; EC=3.6.4.10 {ECO:0000250|UniProtKB:P11021}; Flags: Precursor;
Gene Information: Name=hsp-4; Synonyms=hsp70d; ORFNames=F43E2.8;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the heat shock protein 70 family. .
Key Domains: ATPase_NBD. (IPR043129); BIP_NBD. (IPR042050); Heat_shock_70_CS. (IPR018181); HSP70_C_sf. (IPR029048); HSP70_peptide-bd_sf. (IPR029047)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-4" 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-4 (gene ID: hsp-4, UniProt: P20163) 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.

Gene/protein verification and scope
- Identity and organism: hsp-4 (UniProt P20163) encodes the Caenorhabditis elegans endoplasmic reticulum (ER) HSP70-family chaperone best known as BiP/GRP78. Recent work explicitly treats HSP-4 as one of two C. elegans BiP orthologs (with HSP-3), validating the gene/protein mapping in worm (BiP/HSP70 family; ER-resident chaperone) (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 8-10).
- Family/domains: As an HSP70/BiP ortholog, HSP-4 possesses the canonical HSP70 nucleotide-binding domain and peptide-binding domain architecture that underpins ATP-dependent chaperone cycles; contemporary C. elegans studies reference HSP-4 in this well-established functional context (urban2025functionallydiversifiedcaenorhabditis pages 1-2, waldherr2024endoplasmicreticulumunfolded pages 1-3).

1) Key concepts and definitions with current understanding
- Primary molecular role: HSP-4 is an ER-resident HSP70 (BiP/GRP78) molecular chaperone central to ER proteostasis. Across recent studies, HSP-4 is consistently positioned as an ER chaperone whose expression is induced by the unfolded protein response of the ER (UPRER) and that participates in organismal physiology (growth, reproduction, stress resistance, autophagy) (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11).
- Enzymatic activity concept: HSP-4, as a BiP ortholog, operates through an ATPase-driven chaperone cycle that binds and releases unfolded client polypeptides in the ER lumen; these activities are the hallmark of ER HSP70s and are invoked in recent worm literature when defining HSP-4’s role in ER proteostasis (urban2025functionallydiversifiedcaenorhabditis pages 1-2, waldherr2024endoplasmicreticulumunfolded pages 1-3).
- Localization: HSP-4 is ER-localized. Contemporary analyses use fluorescently tagged endogenous reporters to visualize HSP-4 distribution in vivo, confirming ER association and tissue-specific expression (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 21-25).
- UPRER integration: hsp-4 is a classical UPRER target gene. It is transcriptionally upregulated by the IRE-1/XBP-1 branch, and under some stress modalities, its induction can additionally require ATF-6 and show partial independence from IRE-1/XBP-1, highlighting branch redundancy (waldherr2024endoplasmicreticulumunfolded pages 1-3, xu2024theunfoldedprotein pages 1-1).

2) Recent developments and latest research (2023–2024 priority)
- XBP-1s target and disease-modifying capacity: Transcriptomic analysis in a tauopathy model identified hsp-4 among 116 genes upregulated by constitutively active XBP-1s. Genetic tests showed that upregulation of HSP-4 partially rescues tauopathy, whereas loss of ATF-6 prevents XBP-1s-mediated rescue, demonstrating cross-branch co-dependence for neuroprotective effects (Communications Biology, July 2024; doi:10.1038/s42003-024-06570-2) (waldherr2024endoplasmicreticulumunfolded pages 1-3).
- Replication stress and UPRER crosstalk: Depletion of DNA primases (pri-1/pri-2) activates UPRER with strong germline hsp-4 induction. Notably, hsp-4 activation is partly independent of canonical IRE-1/XBP-1 and requires ATF-6 in this context; IRE-1 and PEK-1 are also activated by primase depletion, indicating multi-branch engagement and functional redundancy (G3, Jan 2024; doi:10.1093/g3journal/jkae017) (xu2024theunfoldedprotein pages 1-1).
- Functional diversification versus paralog HSP-3 (latest mechanistic insights): New work distinguishes HSP-4 from HSP-3. HSP-3 exhibits canonical ER folding roles, while HSP-4 is more specialized in interorganellar signaling and ER-stress mitigation, including regulation of ER-phagy via Sec-62 (C18E9.2) and crosstalk with IRE-1. HSP-4’s effects on autophagy and stress tolerance can occur independently of spliced XBP-1 (Nature Communications, Dec 2025; bioRxiv preprint Jan 2025) (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11, urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedbip pages 21-25). Although 2025 publications, these findings synthesize and extend prior views.

3) Current applications and real-world implementations
- Disease model modulation: HSP-4 upregulation contributes to rescue in C. elegans tauopathy models under XBP-1s activation, indicating potential translational angles for ER proteostasis tuning in neurodegeneration (waldherr2024endoplasmicreticulumunfolded pages 1-3).
- ER stress and autophagy control: Manipulating HSP-4 alters ER-phagy and proteostasis outcomes; HSP-4 loss increases ER-phagy via C18E9.2/Sec-62 and modulates protein-misfolding paralysis. Such genetic manipulations establish HSP-4 as a handle to steer ER homeostasis, with measurable effects on organismal phenotypes (body growth, fecundity, lifespan) (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11, urban2025functionallydiversifiedbip pages 21-25).
- Reporter usage in vivo: Endogenous CRISPR reporters (HSP-4::wrmScarlet) and classical hsp-4::GFP reporters are widely used to monitor ER stress and tissue-specific UPRER activation in live animals, enabling pathway-dissection and drug/genetic screens (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 21-25, xu2024theunfoldedprotein pages 1-1).

4) Expert opinions and analysis from authoritative sources
- Coordinated UPRER branch control: Communications Biology (2024) concludes that robust proteostatic rescue in tauopathy requires ATF-6 alongside IRE-1/XBP-1, placing hsp-4 at the intersection of UPRER branches and emphasizing combinatorial control over ER chaperone gene expression (waldherr2024endoplasmicreticulumunfolded pages 1-3).
- Branch redundancy and context dependence: G3 (2024) demonstrates that the branch logic governing hsp-4 induction depends on stress type and tissue (germline under replication stress), supporting a nuanced model where ATF-6 can drive hsp-4 when IRE-1/XBP-1 is insufficient (xu2024theunfoldedprotein pages 1-1).
- Functional specialization of BiP paralogs: Nature Communications (2025) synthesizes a model in which HSP-3 and HSP-4 have overlapping yet distinct roles, with HSP-4 coupling ER stress to autophagy and signaling via IRE-1/Sec-62 interactions, expanding canonical BiP paradigms in metazoans (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11, urban2025functionallydiversifiedcaenorhabditis pages 1-2).

5) Relevant statistics and data from recent studies
- 116 UPRER targets: Constitutively active XBP-1s upregulated 116 putative targets in C. elegans, with hsp-4 among validated candidates required for tauopathy suppression; loss of function in any one of five selected targets (including hsp-4) disrupted XBP-1s-mediated protection (Communications Biology, 2024; doi:10.1038/s42003-024-06570-2) (waldherr2024endoplasmicreticulumunfolded pages 1-3).
- Tissue/age expression dynamics: Endogenous HSP-4::wrmScarlet reporter analyses reveal low larval expression with increased abundance into adulthood; distinct tissue peaks (e.g., spermatheca) and age-dependent increases were observed, complementing differential dynamics seen for HSP-3 (Nature Communications, 2025; bioRxiv, 2025) (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 21-25).
- UPRER branch requirements under replication stress: Genetic dissection shows hsp-4 induction requires ATF-6 when IRE-1/XBP-1 is partly dispensable; IRE-1 and PEK-1 are activated by primase depletion, and their loss sensitizes animals to hydroxyurea (G3, 2024) (xu2024theunfoldedprotein pages 1-1).

Functional detail: biochemical activity, clients, and pathways
- Chaperone mechanism: As an HSP70/BiP ortholog, HSP-4 participates in ATP-dependent binding/release of unfolded or nascent client polypeptides in the ER lumen, assisting folding and quality control. Contemporary worm studies invoke this canonical mechanism in framing HSP-4’s ER proteostasis role (urban2025functionallydiversifiedcaenorhabditis pages 1-2, waldherr2024endoplasmicreticulumunfolded pages 1-3).
- Client scope and pathway interfaces: While client-specific biochemistry is not comprehensively catalogued in the 2023–2024 worm literature, recent work implicates HSP-4 in controlling IRE-1 availability and ER-phagy via Sec-62 (C18E9.2), demonstrating that HSP-4 influences UPR sensor coupling and downstream autophagy beyond classical folding (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11).
- Developmental and physiological roles: Genetic depletion or mis-expression of hsp-4 alters body growth, fecundity, and lifespan; intestine-specific loss provokes severe phenotypes, while whole-organism loss shortens lifespan. In protein-misfolding models, hsp-4 loss can delay paralysis, whereas overexpression can exacerbate it, underscoring context-specific proteostatic roles (bioRxiv 2025; Nature Communications 2025) (urban2025functionallydiversifiedbip pages 21-25, urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11).
- Stress resistance and disease models: hsp-4 induction is a hallmark of ER stress across modalities. In neurodegeneration models, hsp-4 contributes to XBP-1s-mediated rescue of tau toxicity, consistent with its protective chaperone function when appropriately engaged by UPRER programs (waldherr2024endoplasmicreticulumunfolded pages 1-3).

Experimental tools and localization evidence
- Reporters and localization: hsp-4p::GFP translational reporters and endogenous HSP-4::wrmScarlet fusion alleles demonstrate ER-associated, tissue-specific expression and dynamic induction under stress. Germline-biased induction under replication stress and adult-enriched expression have been documented (G3 2024; Nature Communications 2025; bioRxiv 2025) (xu2024theunfoldedprotein pages 1-1, urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 21-25).

Open questions and implications
- Branch logic and therapeutics: The requirement for ATF-6 alongside IRE-1/XBP-1 to achieve robust disease rescue suggests that therapeutic strategies targeting ER proteostasis may need to co-activate or modulate multiple UPRER branches to realize full benefit, with hsp-4/BiP as a central effector (waldherr2024endoplasmicreticulumunfolded pages 1-3).
- BiP paralog specialization: The emerging division of labor between HSP-3 and HSP-4 raises questions about their differential clienteles, tissue programs, and signaling interfaces (e.g., IRE-1/Sec-62), warranting biochemical and structural investigation in worm systems (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11).

URLs and publication dates (recent)
- Waldherr et al., Communications Biology (July 2024): https://doi.org/10.1038/s42003-024-06570-2 (waldherr2024endoplasmicreticulumunfolded pages 1-3)
- Xu et al., G3 (Jan 2024): https://doi.org/10.1093/g3journal/jkae017 (xu2024theunfoldedprotein pages 1-1)
- Urban et al., Nature Communications (Dec 2025): https://doi.org/10.1038/s41467-025-65998-0 (urban2025functionallydiversifiedcaenorhabditis pages 8-10, urban2025functionallydiversifiedcaenorhabditis pages 10-11, urban2025functionallydiversifiedcaenorhabditis pages 1-2)
- Urban et al., bioRxiv (Jan 2025): https://doi.org/10.1101/2025.01.14.633073 (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedbip pages 21-25, urban2025functionallydiversifiedbip pages 52-53)

Embedded summary of 2024 studies and contexts
| Year | Study (short title) | Key finding relevant to hsp-4/BiP | UPR branch dependency (IRE-1/XBP-1, ATF-6, PEK-1) | Model / assay | Biological context | Journal | URL (month/year) |
|---|---|---|---|---|---|---|---|
| 2024 | XBP-1s transcriptional targets & tauopathy (Waldherr et al.) | hsp-4 (BiP) identified among XBP-1s targets; upregulation of HSP-4 partially rescues tauopathy in C. elegans; loss of ATF-6 prevents XBP-1s-mediated rescue (hsp-4 is protective) (waldherr2024endoplasmicreticulumunfolded pages 1-3) | IRE-1 → XBP-1s transcriptional target; functional rescue requires ATF-6 (branch co-dependence) | Tau transgenic worms; XBP-1s overexpression; transcriptomics; genetic LOF assays | Neurodegeneration / proteostasis (tauopathy rescue) | Communications Biology | https://doi.org/10.1038/s42003-024-06570-2 (Jul 2024) |
| 2024 | Replication-fork stress activates UPR-ER (Xu et al.) | DNA primase depletion strongly induces hsp-4 in the germline; hsp-4 induction can be partly independent of IRE-1/XBP-1 and instead requires ATF-6 under this stress, indicating branch redundancy (xu2024theunfoldedprotein pages 1-1) | IRE-1 and PEK-1 activated by primase depletion; hsp-4 induction shows ATF-6 dependence independent of canonical IRE-1/XBP-1 in this context | hsp-4::GFP translational reporter; genetic primase depletion; hydroxyurea sensitivity assays | Replication stress / genome instability → ER UPR activation (germline-biased) | G3 (Genes-Genomes-Genetics) | https://doi.org/10.1093/g3journal/jkae017 (Jan 2024) |
| 2024 | Neuronal cilia → nonautonomous UPRER (Li et al.) | Inhibition of a neuronal cyclic nucleotide-gated (CNG) channel nonautonomously activates intestinal UPRER and increases lifespan; hsp-4 has low basal expression but is induced in this neuron→intestine axis; IRE-1/XBP-1 required for the nonautonomous signal | IRE-1/XBP-1 required for nonautonomous intestinal UPRER activation (hsp-4 induction part of response) | Neuronal cilia mutants / pharmacological CNG inhibition; hsp-4 expression assays; lifespan measurement | Neuron → intestine longevity signaling via UPRER activation | Proceedings of the National Academy of Sciences (PNAS) | https://doi.org/10.1073/pnas.2321228121 (Jun 2024) |
| 2024 | ER proteostasis & SKN-1 during infection (Gabaldón et al.) | Loss of CDC-48 (ERAD) strongly induces the UPRER and alters SKN-1 activation; hsp-4 regulation is central to the interplay between ER proteostasis and innate immune transcriptional responses | Data and models link hsp-4 regulation to IRE-1/XBP-1 signaling and show UPRER activation can rewire SKN-1 responses | Pathogen infection assays; SKN-1 activation readouts; ERAD/CDC-48 perturbation; hsp-4 transcript/protein measurements | Innate immunity / infection-induced stress; coordination between UPRER and oxidative stress response | Genetics | https://doi.org/10.1093/genetics/iyae131 (Aug 2024) |
| 2024 | HSF-1 deficiency & compensatory UPR (Kovács et al.) | HSF-1 loss in young adults increases thermotolerance via compensatory activation of the UPRER and innate immunity; hsp-4 (UPR marker) is upregulated as part of this compensatory network | UPRER branches (IRE-1/XBP-1 and PEK-1/ATF-6 implicated) are required for the compensatory protection observed when HSF-1 is absent | hsp-4 marker expression; thermotolerance assays; genetic perturbation of UPR branches | Aging and proteostasis compensation; stress resistance in young adults | Aging Cell | https://doi.org/10.1111/acel.14246 (Jun 2024) |

Table: Table summarizing key 2024 C. elegans studies reporting hsp-4/BiP findings, indicating UPR-branch dependencies, experimental models/assays, contexts, and direct DOI links; available context IDs cited where provided.

References

(urban2025functionallydiversifiedcaenorhabditis pages 1-2): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K. F. Donahue, Kristopher Burkewitz, and Matthias C. Truttmann. Functionally diversified caenorhabditis elegans bip orthologs control body growth, reproduction, stress resistance, aging, and autophagy. Nature Communications, Dec 2025. URL: https://doi.org/10.1038/s41467-025-65998-0, doi:10.1038/s41467-025-65998-0. This article has 0 citations and is from a highest quality peer-reviewed journal.
(urban2025functionallydiversifiedcaenorhabditis pages 8-10): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K. F. Donahue, Kristopher Burkewitz, and Matthias C. Truttmann. Functionally diversified caenorhabditis elegans bip orthologs control body growth, reproduction, stress resistance, aging, and autophagy. Nature Communications, Dec 2025. URL: https://doi.org/10.1038/s41467-025-65998-0, doi:10.1038/s41467-025-65998-0. This article has 0 citations and is from a highest quality peer-reviewed journal.
(waldherr2024endoplasmicreticulumunfolded pages 1-3): Sarah M. Waldherr, Marina Han, Aleen D. Saxton, Taylor A. Vadset, Pamela J. McMillan, Jeanna M. Wheeler, Nicole F. Liachko, and Brian C. Kraemer. Endoplasmic reticulum unfolded protein response transcriptional targets of xbp-1s mediate rescue from tauopathy. Communications Biology, Jul 2024. URL: https://doi.org/10.1038/s42003-024-06570-2, doi:10.1038/s42003-024-06570-2. This article has 3 citations and is from a peer-reviewed journal.
(urban2025functionallydiversifiedcaenorhabditis pages 10-11): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K. F. Donahue, Kristopher Burkewitz, and Matthias C. Truttmann. Functionally diversified caenorhabditis elegans bip orthologs control body growth, reproduction, stress resistance, aging, and autophagy. Nature Communications, Dec 2025. URL: https://doi.org/10.1038/s41467-025-65998-0, doi:10.1038/s41467-025-65998-0. This article has 0 citations and is from a highest quality peer-reviewed journal.
(urban2025functionallydiversifiedbip pages 21-25): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, and Matthias C. Truttmann. Functionally diversified bip orthologs control body growth, reproduction, stress resistance, aging, and er-phagy in caenorhabditis elegans. bioRxiv, Jan 2025. URL: https://doi.org/10.1101/2025.01.14.633073, doi:10.1101/2025.01.14.633073. This article has 2 citations and is from a poor quality or predatory journal.
(xu2024theunfoldedprotein pages 1-1): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(urban2025functionallydiversifiedbip pages 29-33): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, and Matthias C. Truttmann. Functionally diversified bip orthologs control body growth, reproduction, stress resistance, aging, and er-phagy in caenorhabditis elegans. bioRxiv, Jan 2025. URL: https://doi.org/10.1101/2025.01.14.633073, doi:10.1101/2025.01.14.633073. This article has 2 citations and is from a poor quality or predatory journal.
(urban2025functionallydiversifiedbip pages 52-53): Nicholas D. Urban, Shannon M. Lacy, Kate M. Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, and Matthias C. Truttmann. Functionally diversified bip orthologs control body growth, reproduction, stress resistance, aging, and er-phagy in caenorhabditis elegans. bioRxiv, Jan 2025. URL: https://doi.org/10.1101/2025.01.14.633073, doi:10.1101/2025.01.14.633073. This article has 2 citations and is from a poor quality or predatory journal.

Citations

waldherr2024endoplasmicreticulumunfolded pages 1-3
xu2024theunfoldedprotein pages 1-1
urban2025functionallydiversifiedcaenorhabditis pages 1-2
urban2025functionallydiversifiedcaenorhabditis pages 8-10
urban2025functionallydiversifiedcaenorhabditis pages 10-11
urban2025functionallydiversifiedbip pages 21-25
urban2025functionallydiversifiedbip pages 29-33
urban2025functionallydiversifiedbip pages 52-53
https://doi.org/10.1038/s42003-024-06570-2
https://doi.org/10.1093/g3journal/jkae017
https://doi.org/10.1038/s41467-025-65998-0
https://doi.org/10.1101/2025.01.14.633073
https://doi.org/10.1073/pnas.2321228121
https://doi.org/10.1093/genetics/iyae131
https://doi.org/10.1111/acel.14246
https://doi.org/10.1038/s41467-025-65998-0,
https://doi.org/10.1038/s42003-024-06570-2,
https://doi.org/10.1101/2025.01.14.633073,
https://doi.org/10.1093/g3journal/jkae017,

📄 View Raw YAML

id: P20163
gene_symbol: hsp-4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: HSP-4 is the major endoplasmic reticulum (ER)-resident HSP70 family
  chaperone in C. elegans, orthologous to mammalian BiP/GRP78. It functions as 
  an ATP-dependent molecular chaperone that assists protein folding and quality 
  control in the ER lumen. HSP-4 is a classical transcriptional target of the 
  unfolded protein response (UPR), primarily induced via the IRE-1/XBP-1 
  pathway, with partial redundancy from the ATF-6 branch. The hsp-4::GFP 
  reporter is the standard marker for ER stress in C. elegans. HSP-4 plays 
  specialized roles in interorganellar signaling, ER-phagy regulation via 
  Sec-62, and stress tolerance, representing functionally diversified activities
  compared to its paralog HSP-3.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation from phylogenetic inference. While mammalian 
        BiP/GRP78 has been reported in nuclear compartments under certain stress
        conditions, HSP-4 in C. elegans is primarily characterized as an ER 
        lumen chaperone. The UniProt record and deep research consistently 
        describe HSP-4 as ER-localized. Nuclear localization may reflect 
        conservation of potential regulatory functions but is not a primary 
        localization in C. elegans.
      action: KEEP_AS_NON_CORE
      reason: While phylogenetically conserved from mammalian BiP, nuclear 
        localization is not a well-documented aspect of HSP-4 function in C. 
        elegans. The protein contains an ER retention signal (HDEL) and is 
        primarily ER-localized according to UniProt and functional studies. This
        annotation may represent an ancestral or minor localization pattern.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation from phylogenetic inference. HSP-4 is primarily 
        ER-localized with an ER retention signal. Some cytoplasmic localization 
        may occur during synthesis or under stress conditions, but the primary 
        functional location is the ER lumen.
      action: KEEP_AS_NON_CORE
      reason: This annotation likely reflects the biosynthetic pathway or minor 
        localization patterns conserved in the HSP70 family. The primary 
        functional location of HSP-4 is the ER lumen, as supported by the HDEL 
        retention signal and functional studies.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4/BiP is an ATPase that uses ATP hydrolysis to drive its 
        chaperone cycle. UniProt assigns EC 3.6.4.10 (ATP-dependent chaperone 
        activity). The deep research confirms that HSP-4 operates through an 
        ATPase-driven chaperone cycle that binds and releases unfolded client 
        polypeptides in the ER lumen.
      action: ACCEPT
      reason: 'ATP hydrolysis is a core molecular function of HSP70 family members
        including BiP/HSP-4. This activity is essential for the chaperone cycle. UniProt
        provides catalytic activity annotation with the reaction: ATP + H2O = ADP
        + phosphate + H(+).'
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: Reaction=ATP + H2O = ADP + phosphate + H(+); 
            Xref=Rhea:RHEA:13065,
        - reference_id: file:worm/hsp-4/hsp-4-deep-research-falcon.md
          supporting_text: HSP-4, as a BiP ortholog, operates through an 
            ATPase-driven chaperone cycle that binds and releases unfolded 
            client polypeptides in the ER lumen
  - term:
      id: GO:0031072
      label: heat shock protein binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP70 family members interact with co-chaperones including J 
        domain-containing proteins (DnaJ/Hsp40) and nucleotide exchange factors.
        HSP-4/BiP requires co-chaperones for efficient substrate recognition and
        ATPase regulation.
      action: ACCEPT
      reason: This is a well-established function for HSP70/BiP family members. 
        UniProt notes that J domain-containing co-chaperones stimulate the 
        ATPase activity and are required for efficient substrate recognition. 
        This interaction is central to the chaperone mechanism.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: J domain-containing co-chaperones stimulate the 
            ATPase activity and are required for efficient substrate recognition
  - term:
      id: GO:0044183
      label: protein folding chaperone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4/BiP is an ER-resident molecular chaperone central to ER 
        proteostasis. It assists protein folding and quality control in the ER 
        lumen. The deep research confirms HSP-4 participates in ATP-dependent 
        binding/release of unfolded or nascent client polypeptides.
      action: ACCEPT
      reason: This is the core molecular function of HSP-4/BiP. It plays a key 
        role in protein folding and quality control in the ER lumen. 
        Overexpression of HSP-4 rescues dendrite morphogenesis defects in ire-1 
        mutants by restoring protein folding capacity (PMID:26052671).
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: Endoplasmic reticulum chaperone that plays a key role
            in protein folding and quality control in the endoplasmic reticulum 
            lumen
        - reference_id: PMID:26052671
          supporting_text: overexpression of hsp-4 in PVD restored normal 
            dendritic branches in ire-1 mutants
  - term:
      id: GO:0036503
      label: ERAD pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: BiP/HSP-4 is involved in ER-associated degradation (ERAD) by 
        recognizing misfolded proteins in the ER. The deep research notes HSP-4 
        involvement in ERAD-related processes and interaction with ERAD 
        components.
      action: ACCEPT
      reason: BiP/HSP-4 functions in ERAD by recognizing and retaining misfolded
        proteins for degradation. PMID:12186849 demonstrates genetic interaction
        between hsp-4 and ERAD component sel-1, and shows that RNAi of sel-1 
        activates the hsp-4::gfp ER stress reporter in an xbp-1-dependent 
        manner.
      supported_by:
        - reference_id: PMID:12186849
          supporting_text: RNAi of sel-1, the C. elegans homologue of the yeast 
            ERAD gene HRD3
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4 is a soluble ER lumen protein, not a membrane protein. It 
        may associate with ER membrane peripherally through interactions with 
        membrane-bound clients or ERAD components, but is not an integral 
        membrane protein.
      action: MARK_AS_OVER_ANNOTATED
      reason: This term is overly broad and imprecise. HSP-4/BiP is a soluble 
        protein in the ER lumen with a HDEL retention signal. While it may 
        interact with membrane-associated substrates, it is not itself a 
        membrane protein. The more specific terms GO:0005788 (ER lumen) and 
        GO:0034663 (ER chaperone complex) are more appropriate.
      proposed_replacement_terms:
        - id: GO:0005788
          label: endoplasmic reticulum lumen
  - term:
      id: GO:0042026
      label: protein refolding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP70/BiP chaperones assist in protein refolding as part of their
        quality control function. This is a well-established activity for the 
        HSP70 family.
      action: ACCEPT
      reason: Protein refolding is a core function of HSP70 family chaperones 
        including BiP/HSP-4. The ATP-driven chaperone cycle allows iterative 
        binding and release of substrates to promote proper folding.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: The chaperone activity is regulated by ATP-induced 
            allosteric coupling of the nucleotide-binding (NBD) and substrate- 
            binding (SBD) domains
  - term:
      id: GO:0034663
      label: endoplasmic reticulum chaperone complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4/BiP functions within ER chaperone complexes with 
        co-chaperones and other quality control machinery. This is supported by 
        both phylogenetic inference and ISS evidence from PMID:11779465.
      action: ACCEPT
      reason: HSP-4 is a core component of the ER chaperone machinery, 
        functioning with co-chaperones and other quality control proteins. This 
        localization is well-supported by the protein's known function.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: J domain-containing co-chaperones stimulate the 
            ATPase activity and are required for efficient substrate recognition
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4 is localized to the ER lumen. This is the primary 
        functional location of BiP/GRP78 homologs. The protein contains a signal
        peptide and HDEL ER retention motif.
      action: ACCEPT
      reason: This is the primary and well-established localization of 
        HSP-4/BiP. UniProt clearly states ER lumen localization. The protein has
        a signal peptide (aa 1-17) and HDEL ER retention motif (aa 654-657).
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
        - reference_id: PMID:26052671
          supporting_text: we first examined the subcellular localization of 
            HSP-4 and found that HSP-4::GFP was exclusively localized in the PVD
            soma
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HSP-4/BiP is a classical UPR target gene and effector. Its 
        expression is strongly induced during ER stress, and the hsp-4::GFP 
        reporter is the standard UPR marker in C. elegans. HSP-4 also regulates 
        UPR signaling through interaction with IRE-1.
      action: ACCEPT
      reason: HSP-4 is both a target and effector of the ER UPR. It is 
        transcriptionally induced by the IRE-1/XBP-1 pathway during ER stress. 
        Multiple publications establish hsp-4 as a core UPR marker and 
        functional component.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 
            mRNA for UPR gene transcription and survival upon ER stress
        - reference_id: PMID:12186849
          supporting_text: the signaling pathway initiated by IRE1 exerts nearly
            complete control over the induction of well-characterized components
            of ER client protein processing machinery, such as BiP (hsp-4)
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation from UniProt keyword mapping. HSP-4 binds ATP as 
        part of its chaperone cycle. This is a parent term of ATP binding.
      action: ACCEPT
      reason: This is a correct but general annotation. HSP-4 has 
        well-characterized ATP binding and hydrolysis activities. UniProt 
        provides detailed ATP binding site information (residues 38-41, 99, 
        229-231, 295-302, 366-369).
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation from automated methods. HSP-4 contains a 
        well-characterized ATP binding domain. ATP binding is essential for the 
        chaperone cycle.
      action: ACCEPT
      reason: ATP binding is a core molecular function of HSP-4/BiP. UniProt 
        provides detailed annotation of ATP binding sites and the protein has 
        crystal structure data for the peptide-binding domain (PDB:2OP6).
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation from UniProt subcellular location mapping. This 
        duplicates the IBA annotation but from a different source. Both are 
        correct.
      action: ACCEPT
      reason: ER lumen localization is well-established for HSP-4/BiP. Multiple 
        evidence types supporting the same annotation is appropriate.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation from keyword mapping. HSP-4 has ATPase activity 
        (hydrolyzes ATP). This is a parent term of ATP hydrolysis activity.
      action: ACCEPT
      reason: This is a correct but general annotation. HSP-4 is an ATPase with 
        hydrolase activity. The more specific term GO:0016887 (ATP hydrolysis 
        activity) is also annotated.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: EC=3.6.4.10 {ECO:0000250|UniProtKB:P11021}
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation from automated methods. This duplicates the IBA 
        annotation for ATP hydrolysis activity. Both are correct.
      action: ACCEPT
      reason: ATP hydrolysis is a core molecular function of HSP-4/BiP, 
        essential for the chaperone cycle. Multiple evidence types are 
        appropriate.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: Reaction=ATP + H2O = ADP + phosphate + H(+); 
            Xref=Rhea:RHEA:13065,
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA annotation from ARBA machine learning. This duplicates other 
        annotations for UPR involvement. HSP-4 is a well-established UPR 
        component.
      action: ACCEPT
      reason: HSP-4 involvement in the ER UPR is well-established. Multiple 
        evidence sources supporting this annotation is appropriate.
      supported_by:
        - reference_id: PMID:12186849
          supporting_text: BiP (hsp-4), protein disulfide isomerases, and 
            4-prolyl hydroxylases
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEP
    original_reference_id: PMID:11779465
    review:
      summary: IEP annotation based on expression pattern. Shen et al. (2001) 
        established that hsp-4 is a UPR target gene regulated by ire-1/xbp-1 
        signaling in C. elegans.
      action: ACCEPT
      reason: PMID:11779465 is a foundational paper establishing the UPR pathway
        in C. elegans. It demonstrates that ire-1-mediated splicing of xbp-1 is 
        required for UPR gene transcription including hsp-4.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 
            mRNA for UPR gene transcription and survival upon ER stress
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEP
    original_reference_id: PMID:11780124
    review:
      summary: IEP annotation based on expression pattern. Calfon et al. (2002) 
        demonstrated that xbp-1 processing by IRE1 is conserved in C. elegans 
        and activates UPR target genes.
      action: ACCEPT
      reason: PMID:11780124 demonstrates that IRE1-mediated XBP-1 mRNA splicing 
        activates UPR target genes in C. elegans, establishing the conserved 
        IRE1/XBP-1 pathway.
      supported_by:
        - reference_id: PMID:11780124
          supporting_text: mutations in either ire-1 or the 
            transcription-factor-encoding xbp-1 gene abolished the UPR in 
            Caenorhabditis elegans
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEP
    original_reference_id: PMID:18216284
    review:
      summary: IEP annotation based on expression pattern. Uccelletti et al. 
        (2008) showed that ER stress induced by tunicamycin or high temperature 
        results in increased hsp-4 transcription, dependent on both ire-1 and 
        atf-6.
      action: ACCEPT
      reason: PMID:18216284 demonstrates that hsp-4 induction during ER stress 
        requires both IRE-1 and ATF-6 sensors, showing branch redundancy in UPR 
        regulation.
      supported_by:
        - reference_id: PMID:18216284
          supporting_text: ER stress induced by tunicamycin or high temperature 
            resulted in increased transcription of apy-1. This increase was not 
            observed in C. elegans mutants defective in ire-1 or atf-6
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: HEP
    original_reference_id: PMID:12186849
    review:
      summary: HEP annotation based on expression pattern from high-throughput 
        experiment. Urano et al. (2002) used microarray analysis to characterize
        UPR target genes and showed hsp-4 induction is xbp-1-dependent.
      action: ACCEPT
      reason: PMID:12186849 provides genome-wide evidence that hsp-4 is a 
        robustly induced UPR target gene dependent on xbp-1. The study used cDNA
        microarrays and showed hsp-4 induction in wild-type but not xbp-1 
        mutants.
      supported_by:
        - reference_id: PMID:12186849
          supporting_text: the signaling pathway initiated by IRE1 exerts nearly
            complete control over the induction of well-characterized components
            of ER client protein processing machinery, such as BiP (hsp-4)
  - term:
      id: GO:0005791
      label: rough endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: PMID:26052671
    review:
      summary: IDA annotation based on direct assay. Wei et al. (2015) showed 
        that HSP-4::GFP co-localized with the rough ER marker TRAM in PVD 
        neurons, demonstrating localization to the rough ER.
      action: ACCEPT
      reason: PMID:26052671 provides direct imaging evidence that HSP-4 
        co-localizes with the rough ER marker TRAM, consistent with BiP's known 
        function in nascent protein folding.
      supported_by:
        - reference_id: PMID:26052671
          supporting_text: we first examined the subcellular localization of 
            HSP-4 and found that HSP-4::GFP was exclusively localized in the PVD
            soma
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEP
    original_reference_id: PMID:15280428
    review:
      summary: IEP annotation based on expression pattern. Yoneda et al. (2004) 
        demonstrated compartment-specific stress responses and showed hsp-4 
        induction is specific to ER stress, not mitochondrial stress.
      action: ACCEPT
      reason: PMID:15280428 establishes the specificity of hsp-4 induction to ER
        stress, distinguishing it from mitochondrial UPR. This supports HSP-4's 
        specific role in ER proteostasis.
      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
  - term:
      id: GO:0034663
      label: endoplasmic reticulum chaperone complex
    evidence_type: ISS
    original_reference_id: PMID:11779465
    review:
      summary: ISS annotation based on sequence similarity. HSP-4 functions in 
        ER chaperone complexes similar to mammalian BiP.
      action: ACCEPT
      reason: HSP-4 is orthologous to mammalian BiP, which functions in ER 
        chaperone complexes. The functional conservation is supported by rescue 
        experiments and pathway conservation.
      supported_by:
        - reference_id: UniProt:P20163
          supporting_text: Belongs to the heat shock protein 70 family
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:24068940
    review:
      summary: IPI annotation based on physical interaction. Glover-Cutter et 
        al. (2013) showed that SKN-1/Nrf transcription factor regulates hsp-4 
        during ER stress. This annotation may reflect interaction data from ChIP
        or co-IP experiments.
      action: UNDECIDED
      reason: This annotation suggests HSP-4 physically interacts with 
        transcription factors. While SKN-1 regulates hsp-4 transcription, HSP-4 
        is an ER lumen protein and direct binding to transcription factors would
        be unexpected. The annotation may reflect a database error or indirect 
        interaction. Further review of the original paper is needed to verify 
        the specific interaction claimed.
      additional_reference_ids:
        - PMID:24068940
      supported_by:
        - reference_id: PMID:24068940
          supporting_text: Sep 12. Integration of the unfolded protein and 
            oxidative stress responses through SKN-1/Nrf.
  - term:
      id: GO:0006457
      label: protein folding
    evidence_type: NAS
    review:
      summary: Added to align core_functions with existing annotations.
      action: NEW
      reason: Core function term not present in existing_annotations.
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: IBA annotations from PANTHER phylogenetic trees provide 
          evolutionary evidence for HSP-4 function
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings:
      - statement: UniProt keyword mappings provide IEA annotations
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings:
      - statement: UniProt subcellular location provides localization 
          annotations
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings:
      - statement: Machine learning predictions support UPR involvement
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings:
      - statement: Combined evidence supports ATP binding and hydrolysis 
          functions
  - id: PMID:11779465
    title: Complementary signaling pathways regulate the unfolded protein 
      response and are required for C. elegans development.
    findings:
      - statement: Established that C. elegans requires ire-1-mediated splicing 
          of xbp-1 for UPR gene transcription
        supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 
          mRNA for UPR gene transcription and survival upon ER stress
      - statement: Demonstrated that ire-1/xbp-1 and pek-1 act in complementary 
          pathways essential for development
        supporting_text: ire-1/xbp-1 acts with pek-1, a protein kinase that 
          mediates translation attenuation, in complementary pathways that are 
          essential for worm development and survival
      - statement: hsp-4 identified as a UPR target gene
        supporting_text: C. elegans requires ire-1-mediated splicing of xbp-1 
          mRNA for UPR gene transcription and survival upon ER stress
  - id: PMID:11780124
    title: IRE1 couples endoplasmic reticulum load to secretory capacity by 
      processing the XBP-1 mRNA.
    findings:
      - statement: Demonstrated conserved IRE1-dependent XBP-1 mRNA splicing in 
          C. elegans
      - statement: Established XBP-1 as a key UPR transcription factor
  - id: PMID:12186849
    title: A survival pathway for Caenorhabditis elegans with a blocked unfolded
      protein response.
    findings:
      - statement: Genome-wide survey showing hsp-4 (BiP) is robustly induced 
          during UPR in xbp-1-dependent manner
      - statement: Established hsp-4::gfp as a standard ER stress reporter
      - statement: Demonstrated genetic interactions between UPR components and 
          ERAD genes
  - id: PMID:15280428
    title: Compartment-specific perturbation of protein handling activates genes
      encoding mitochondrial chaperones.
    findings:
      - statement: Demonstrated that hsp-4 induction is specific to ER stress, 
          not mitochondrial stress
      - statement: Established compartment-specific UPR signaling
  - id: PMID:18216284
    title: APY-1, a novel Caenorhabditis elegans apyrase involved in unfolded 
      protein response signalling and stress responses.
    findings:
      - statement: Showed that ER stress by tunicamycin or heat induces hsp-4 
          transcription
      - statement: Demonstrated requirement of both ire-1 and atf-6 for full UPR
          induction
  - id: PMID:24068940
    title: Integration of the unfolded protein and oxidative stress responses 
      through SKN-1/Nrf.
    findings:
      - statement: Showed SKN-1/Nrf regulates transcription of UPR genes 
          including hsp-4
      - statement: Demonstrated integration of oxidative and ER stress responses
  - id: PMID:26052671
    title: The unfolded protein response is required for dendrite morphogenesis.
    findings:
      - statement: Demonstrated HSP-4::GFP co-localizes with rough ER marker 
          TRAM
      - statement: Showed that HSP-4 overexpression rescues dendritic defects in
          ire-1 mutants
      - statement: Established HSP-4's role in protein folding capacity for 
          dendrite development
  - id: urban2025functionallydiversifiedcaenorhabditis
    title: Functionally diversified Caenorhabditis elegans BiP orthologs control
      body growth, reproduction, stress resistance, aging, and autophagy
    findings:
      - statement: Demonstrated functional diversification between HSP-3 and 
          HSP-4
      - statement: HSP-4 specialized for interorganellar signaling and ER-stress
          mitigation
      - statement: HSP-4 regulates ER-phagy via Sec-62 (C18E9.2) and crosstalk 
          with IRE-1
  - id: waldherr2024endoplasmicreticulumunfolded
    title: Endoplasmic reticulum unfolded protein response transcriptional 
      targets of xbp-1s mediate rescue from tauopathy
    findings:
      - statement: hsp-4 identified among 116 XBP-1s upregulated genes
      - statement: HSP-4 upregulation partially rescues tauopathy
      - statement: ATF-6 required alongside IRE-1/XBP-1 for full neuroprotection
  - id: xu2024theunfoldedprotein
    title: The unfolded protein response of the endoplasmic reticulum protects 
      Caenorhabditis elegans against DNA damage caused by stalled replication 
      forks
    findings:
      - statement: DNA primase depletion induces germline hsp-4 expression
      - statement: hsp-4 induction can be ATF-6 dependent and partly IRE-1/XBP-1
          independent
      - statement: Demonstrated context-dependent UPR branch requirements
core_functions:
  - description: HSP-4/BiP is the major ER-resident HSP70 chaperone that assists
      protein folding in the ER lumen. It uses ATP-dependent cycles of binding 
      and release to promote proper folding of nascent and unfolded proteins. 
      This is the primary molecular function of HSP-4.
    molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    directly_involved_in:
      - id: GO:0030968
        label: endoplasmic reticulum unfolded protein response
      - id: GO:0036503
        label: ERAD pathway
    locations:
      - id: GO:0005788
        label: endoplasmic reticulum lumen
    supported_by:
      - reference_id: UniProt:P20163
        supporting_text: Endoplasmic reticulum chaperone that plays a key role 
          in protein folding and quality control in the endoplasmic reticulum 
          lumen
      - reference_id: PMID:26052671
        supporting_text: overexpression of hsp-4 in PVD restored normal 
          dendritic branches in ire-1 mutants
  - description: ATP hydrolysis drives the HSP-4 chaperone cycle. Allosteric 
      coupling between the nucleotide-binding and substrate-binding domains 
      allows regulated binding and release of client proteins.
    molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005788
        label: endoplasmic reticulum lumen
    supported_by:
      - reference_id: UniProt:P20163
        supporting_text: Reaction=ATP + H2O = ADP + phosphate + H(+); 
          Xref=Rhea:RHEA:13065,
  - description: HSP-4 binds ATP as part of its chaperone mechanism, using 
      allosteric regulation between nucleotide-binding and substrate-binding 
      domains to control substrate binding affinity.
    molecular_function:
      id: GO:0005524
      label: ATP binding
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005788
        label: endoplasmic reticulum lumen
    supported_by:
      - reference_id: UniProt:P20163
        supporting_text: GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW
proposed_new_terms: []
suggested_questions:
  - question: What are the specific client proteins of HSP-4 in C. elegans? 
      While the chaperone function is well-established, specific substrates 
      beyond DMA-1 are not well characterized.
    experts: []
  - question: How does HSP-4 differ functionally from HSP-3 in terms of client 
      specificity and tissue-specific roles? Recent work suggests functional 
      diversification but the mechanistic basis is unclear.
    experts: []
  - question: What is the basis for the GO:0061629 annotation (transcription 
      factor binding)? As an ER lumen protein, direct interaction with 
      transcription factors would be unusual.
    experts: []
suggested_experiments:
  - description: Proximity labeling (BioID/TurboID) to identify HSP-4 client 
      proteins and interaction partners in vivo under basal and stress 
      conditions.
    experiment_type: proteomics
    hypothesis: HSP-4 has specific client proteins distinct from HSP-3
  - description: Comparative proteomics of hsp-4 vs hsp-3 mutants to identify 
      specific clients and pathway dependencies of each paralog.
    experiment_type: comparative proteomics
    hypothesis: HSP-3 and HSP-4 have distinct client protein profiles
  - description: Live imaging of endogenous HSP-4 reporters under various stress
      conditions to understand tissue-specific and temporal dynamics of 
      expression.
    experiment_type: live imaging
    hypothesis: HSP-4 expression shows tissue-specific patterns during stress
tags:
  - caeel-proteostasis
  - caeel-upr-stress

hsp-4

Gene Description

Existing Annotations Review

Core Functions

HSP-4/BiP is the major ER-resident HSP70 chaperone that assists protein folding in the ER lumen. It uses ATP-dependent cycles of binding and release to promote proper folding of nascent and unfolded proteins. This is the primary molecular function of HSP-4.

ATP hydrolysis drives the HSP-4 chaperone cycle. Allosteric coupling between the nucleotide-binding and substrate-binding domains allows regulated binding and release of client proteins.

HSP-4 binds ATP as part of its chaperone mechanism, using allosteric regulation between nucleotide-binding and substrate-binding domains to control substrate binding affinity.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

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:

Output

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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