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The hsp-3 gene (also known as hsp70c, ORF name C15H9.6; UniProt P27420) encodes Heat Shock 70 kDa Protein C in Caenorhabditis elegans. HSP-3 is a member of the heat shock protein 70 (HSP70) family and is one of two C. elegans orthologs of mammalian BiP/GRP78 (the binding immunoglobulin protein), the other being HSP-4 (urban2025functionallydiversifiedcaenorhabditis pages 1-2, shen2001complementarysignalingpathways pages 2-3). While mammals possess a single BiP gene, C. elegans has undergone a gene duplication resulting in two functionally diversified BiP paralogs that share high sequence similarity but have distinct roles in endoplasmic reticulum (ER) proteostasis and organismal physiology (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 1-5).
HSP-3 functions as a canonical ER-resident HSP70 chaperone primarily responsible for de novo protein folding and the refolding of misfolded proteins within the ER lumen (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 8-10). Like its mammalian counterpart BiP, HSP-3 contains an N-terminal ATPase/nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain, consistent with its InterPro domain annotations (ATPase_NBD, BIP_NBD, HSP70_C_sf, HSP70_peptide-bd_sf). The protein cycles between ATP-bound (low-affinity, fast-exchange) and ADP-bound (high-affinity, slow-exchange) states to bind and release unfolded or misfolded client polypeptides translocated into the ER, thereby assisting their productive folding (urban2025functionallydiversifiedbip pages 29-33, truttmann2016thecaenorhabditiselegans pages 8-11).
Recent work by Urban et al. (2025) has clarified that, compared to its paralog HSP-4, HSP-3 operates more directly as a protein refolding chaperone, while HSP-4 has become more specialized for interorganellar signaling, ER stress mitigation, and adaptive transcriptional programs (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 8-10). This functional diversification represents a significant conceptual advance in understanding how duplicated BiP genes partition ER proteostasis functions.
HSP-3 is a direct substrate of the Fic-domain AMPylase FIC-1, the C. elegans ortholog of mammalian FICD/HYPE. Mass spectrometry identified threonine 176 (Thr176) within the nucleotide-binding domain as the specific AMPylation site, a modification that covalently attaches an AMP moiety to the protein (truttmann2016thecaenorhabditiselegans pages 13-14, truttmann2016thecaenorhabditiselegans pages 11-13, camara2022hypemediatedampylationas pages 37-41). Notably, this site differs from the mammalian BiP AMPylation sites (Ser365/Thr366 and Thr518), indicating species-specific regulatory mechanisms (camara2022hypemediatedampylationas pages 37-41). HSP-4, by contrast, was not identified as a FIC-1 AMPylation target, demonstrating selectivity among the two BiP paralogs (camara2022hypemediatedampylationas pages 37-41, chatterjee2021ficandnonfic pages 14-15). While the precise consequences of Thr176 AMPylation for HSP-3 chaperone activity remain to be fully elucidated, FIC-1 is proposed to act as a "soft" regulator of BiP-dependent ER proteostasis (truttmann2016thecaenorhabditiselegans pages 13-14, chatterjee2021ficandnonfic pages 14-15).
HSP-3 is localized to the ER lumen, consistent with its possession of an N-terminal signal peptide (precursor) and a C-terminal KDEL ER-retention motif (couillault2012auprindependentinfectionspecific pages 7-8, shen2001complementarysignalingpathways pages 2-3). This distinguishes it from HSP-4, which carries an HDEL retention signal (shen2001complementarysignalingpathways pages 2-3). The ER-lumenal localization restricts HSP-3's direct access to cytosolic proteins, confining its primary chaperone activity to the secretory pathway (urban2025functionallydiversifiedbip pages 29-33). Fluorescent protein fusion reporters (HSP-3::wrmScarlet) with tags inserted immediately upstream of the XDEL motif confirmed functional ER localization and allowed visualization of tissue-specific expression patterns (urban2025functionallydiversifiedbip pages 14-18).
HSP-3 is broadly expressed throughout the worm body, with particularly high abundance in the intestine and neurons in early adulthood (urban2025functionallydiversifiedbip pages 18-21). Expression increases in response to ER stress predominantly in these tissues (urban2025functionallydiversifiedbip pages 18-21). Germline expression is also functionally important: germline-specific ablation of hsp-3 shortens lifespan (urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25). Intriguingly, intestine-specific loss of hsp-3 does not significantly alter lifespan, and pan-neuronal loss has modest effects, suggesting that the germline is a critical tissue for HSP-3-dependent longevity control (urban2025functionallydiversifiedcaenorhabditis pages 5-8).
HSP-3 protein levels are notably higher than HSP-4 throughout larval development and in day 1 adults, peaking during the L3/L4 developmental stages (approximately 48 hours post-development) (urban2025functionallydiversifiedbip pages 14-18, urban2025functionallydiversifiedcaenorhabditis pages 1-2). HSP-3 abundance then decreases upon entry into adulthood, though it increases again later in life, with maximum adult levels around day 5 (urban2025functionallydiversifiedcaenorhabditis pages 1-2). This contrasts with HSP-4, whose levels are minimal during larval stages but rise substantially during adulthood, peaking around day 10 (urban2025functionallydiversifiedcaenorhabditis pages 1-2).
HSP-3 is both a target gene and a regulatory component of the ER unfolded protein response. The UPR^ER in C. elegans operates through three conserved sensor pathways: IRE-1/XBP-1, PEK-1 (PERK ortholog), and ATF-6.
The AMPylase FIC-1 modulates HSP-3 activity at the post-translational level. Genetic deletion of fic-1 rescues the developmental arrest caused by hsp-3 depletion in polyglutamine-expressing animals, indicating that FIC-1-mediated AMPylation normally restrains compensatory proteostasis responses (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4). In fic-1-deficient worms, loss of hsp-3 triggers upregulation of the cytosolic HSP70 chaperone F44E5.4 through UPR^ER signaling, which is sufficient to suppress polyQ toxicity. This requires both IRE-1 and ATF-6, as knockdown of either blocks F44E5.4 upregulation (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 14-16).
A distinct and surprising function of HSP-3 was uncovered by Couillault et al. (2012): HSP-3 plays a UPR-independent, infection-specific role in the epidermal innate immune response to fungal infection by Drechmeria coniospora (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7). Epistasis analysis placed HSP-3 genetically downstream of the Tribbles-like kinase NIPI-3 and upstream of (or parallel to) the protein kinase C delta TPA-1 in the regulation of the antimicrobial peptide gene nlp-29 (couillault2012auprindependentinfectionspecific pages 5-7). This immune function is specific to infection and is not shared with HSP-4, nor does it involve the canonical UPR. HSP-3 does not affect nlp-29 induction by non-immune stressors such as wounding, salt stress, or PMA treatment (couillault2012auprindependentinfectionspecific pages 5-7). The precise mechanism by which an ER-resident chaperone signals in an infection-specific immune pathway remains an open question, with the authors suggesting that HSP-3 may function outside the ER in some contexts despite possessing a KDEL retention signal (couillault2012auprindependentinfectionspecific pages 7-8).
In an elegant 2024 study, Shi et al. identified BiP (encoded by hsp-3/hsp-4) as a temperature sensor mediating temperature-induced germline sex reversal in C. elegans (shi2024identificationofbip pages 9-10). At warmer temperatures (30°C), increased ER protein-folding demand sequesters BiP, reducing the pool of free BiP available in the germline. This reduction in available BiP leads to ERAD-dependent degradation of the oocyte fate-driving factor TRA-2, thereby promoting male (sperm) germline fate. The mechanism demonstrates that BiP transduces temperature information into a germline sex-governing signal, providing mechanistic insight into how genotypic and temperature-dependent sex determination can coexist (shi2024identificationofbip pages 9-10).
HSP-3 depletion has pronounced effects in C. elegans models of protein aggregation diseases. In polyglutamine (polyQ)-expressing worms, hsp-3 knockdown causes developmental arrest and worsens fitness and lifespan decline (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4, pelt2025lossoffic1mediated pages 10-14). Transcriptomic analysis revealed that hsp-3 loss upregulates molecular chaperones (hsp-90, F44E5.4/F44E5.5, small HSPs), ERAD components, and glutathione S-transferases, while downregulating reproduction and lysosomal function genes (pelt2025lossoffic1mediated pages 14-16, pelt2025lossoffic1mediated pages 10-14). HSP-3 overexpression, however, does not increase paralysis in amyloid-β expressing worms, in contrast to HSP-4 overexpression, indicating compartmentalized functional roles in neurodegenerative contexts (urban2025functionallydiversifiedbip pages 29-33).
A comprehensive analysis by Urban et al. (2025, Nature Communications) demonstrated that HSP-3 and HSP-4 have distinct roles in longevity (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25):
The following table compares the two BiP orthologs across major functional dimensions:
| Feature | HSP-3 | HSP-4 |
|---|---|---|
| Gene / ortholog identity | BiP/GRP78-family ER-resident HSP70 chaperone encoded by hsp-3; one of two C. elegans BiP paralogs (urban2025functionallydiversifiedcaenorhabditis pages 1-2, shen2001complementarysignalingpathways pages 7-8) | BiP/GRP78-family ER-resident HSP70 chaperone encoded by hsp-4; paralog of hsp-3 and canonical UPR reporter target in many studies (urban2025functionallydiversifiedcaenorhabditis pages 1-2, shen2001complementarysignalingpathways pages 7-8) |
| ER retention motif | KDEL ER-retention motif reported for HSP-3 (couillault2012auprindependentinfectionspecific pages 7-8, shen2001complementarysignalingpathways pages 2-3) | HDEL ER-retention motif reported for HSP-4 (shen2001complementarysignalingpathways pages 2-3) |
| Basal expression level | Higher basal expression than HSP-4; hsp-3 has ~5-fold higher basal expression and HSP-3 protein exceeds HSP-4 through development and in day-1 adults (urban2025functionallydiversifiedbip pages 14-18, shen2001complementarysignalingpathways pages 2-3) | Lower basal expression than HSP-3 during development; minimal in larval stages relative to HSP-3 (urban2025functionallydiversifiedbip pages 14-18, urban2025functionallydiversifiedcaenorhabditis pages 1-2) |
| Stress inducibility | Induced by ER stress, but more modestly than hsp-4; DTT induced hsp-3 ~2-fold in early UPR work (shen2001complementarysignalingpathways pages 2-3) | Strongly stress inducible; DTT induced hsp-4 ~9-fold, making it the more classic inducible UPR target (shen2001complementarysignalingpathways pages 2-3) |
| Primary function | Functions as a more canonical ER HSP70 chaperone for de novo protein folding and misfolded protein refolding; especially important for developmental protein quality control (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 8-10) | Shares ER folding function but appears more specialized for ER stress mitigation, signaling integration, and adaptive proteostasis programs rather than primarily direct refolding (urban2025functionallydiversifiedbip pages 18-21, urban2025functionallydiversifiedcaenorhabditis pages 8-10) |
| Tissue-enriched expression | Broadly expressed; in early adulthood HSP-3 is especially abundant in intestine and neurons (urban2025functionallydiversifiedbip pages 18-21) | Also induced in intestine and neurons under ER stress; later-life expression becomes more prominent than during larval stages (urban2025functionallydiversifiedbip pages 18-21, urban2025functionallydiversifiedcaenorhabditis pages 1-2) |
| Intestine-specific roles | Intestine-specific loss of hsp-3 did not significantly alter lifespan in the 2025 study (urban2025functionallydiversifiedcaenorhabditis pages 5-8) | Intestinal hsp-4 loss shortened lifespan and caused severe defects including early death/matricide, indicating a stronger intestinal homeostatic requirement (urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) |
| Germline-specific roles | Germline-specific ablation shortens lifespan, showing a germline requirement for organismal aging control (urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) | Germline loss also shortens lifespan, in some analyses more severely than hsp-3 loss (urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) |
| Neuronal roles | Pan-neuronal loss had little lifespan effect, but HSP-3 is strongly expressed in neurons and participates in neuronal/organismal ER proteostasis programs (urban2025functionallydiversifiedbip pages 18-21, urban2025functionallydiversifiedcaenorhabditis pages 5-8) | Neuronal expression is also part of ER stress responses; hsp-4 is a major downstream effector in proteostasis-related neuronal disease models such as tauopathy rescue by XBP-1s (urban2025functionallydiversifiedbip pages 18-21) |
| Age-dependent expression | Peaks during L3/L4 development, remains above HSP-4 in day-1 adults, then declines on entry into adulthood; later peaks around day 5 adults in the 2025 study (urban2025functionallydiversifiedbip pages 14-18, urban2025functionallydiversifiedcaenorhabditis pages 1-2) | Low during larval development, rises strongly in adulthood, with peak abundance later than HSP-3 (around day 10 adults in the 2025 study) (urban2025functionallydiversifiedcaenorhabditis pages 1-2) |
| Role in basal UPR regulation | Basal expression requires IRE-1; during ER stress, upregulation depends strongly on IRE-1/XBP-1 (urban2025functionallydiversifiedbip pages 18-21, shen2001complementarysignalingpathways pages 7-8) | Basal expression also depends on IRE-1; stress-induced regulation is more complex, involving IRE-1 and context-dependent input from ATF-6, while PEK-1 can negatively regulate some HSP-4 responses (urban2025functionallydiversifiedbip pages 18-21) |
| Differential engagement with UPR branches | Loss of hsp-3 elicits UPR and stress-response transcription; in polyQ settings, protective compensation in fic-1 mutants requires IRE-1, ATF-6, and PEK-1 downstream signaling (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 14-16) | Loss of hsp-4 more strongly resembles overt UPRER activation and is more tightly integrated with the broader three-sensor UPR network (urban2025functionallydiversifiedbip pages 18-21) |
| Role in aging / lifespan | Loss shortens lifespan more severely than hsp-4 loss; overexpression of HSP-3 extends lifespan; particularly critical during larval development for later-life health (urban2025functionallydiversifiedbip pages 1-5, urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) | Loss also shortens lifespan, but HSP-4 is more critical during adulthood and in intestine-centered longevity control (urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) |
| Relationship to dietary restriction / insulin-signaling longevity | 2025 work indicates HSP-3 and HSP-4 differentially regulate dietary-restriction and reduced-insulin-signaling longevity; hsp-3 loss can enhance lifespan in daf-2 mutants, implying non-identical interaction with IIS (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8) | Also participates in DR/IIS longevity regulation, but with distinct tissue/time requirements from HSP-3 (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8) |
| FIC-1 AMPylation | Direct FIC-1 target; AMPylated at Thr176 in the nucleotide-binding domain, indicating post-translational regulation of HSP-3 activity/state (truttmann2016thecaenorhabditiselegans pages 13-14, truttmann2016thecaenorhabditiselegans pages 11-13, chatterjee2021ficandnonfic pages 14-15) | No comparable FIC-1 AMPylation evidence was identified in the cited studies; HSP-4 was not highlighted as the FIC-1-modified BiP paralog (camara2022hypemediatedampylationas pages 37-41, chatterjee2021ficandnonfic pages 14-15) |
| Innate immunity role | Has a distinct UPR-independent infection-specific role in epidermal antifungal signaling; acts genetically downstream of nipi-3 and upstream of or parallel to tpa-1 to regulate nlp-29 induction (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) | Does not share the same infection-specific immune role; can partly compensate in some contexts but was not assigned the same nlp-29 regulatory function (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) |
| PolyQ / proteotoxic stress phenotypes | hsp-3 depletion causes developmental arrest and worsens polyQ toxicity; fic-1 deletion can rescue this by activating UPRER-linked compensatory chaperone programs (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4, pelt2025lossoffic1mediated pages 10-14) | hsp-4 depletion also perturbs ER homeostasis, but transcriptomic and signaling consequences are distinct and complementary to hsp-3 loss (pelt2025lossoffic1mediated pages 1-2) |
| ER-phagy / autophagy | Participates in BiP-controlled ER proteostasis and ER-phagy-related phenotypes, but hsp-3 loss alone did not specifically induce autophagy in the 2025 work (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 33-36) | More clearly linked to autophagy/ER-phagy control; hsp-4 knockdown specifically induced autophagy and HSP-4 was linked to ER-phagy signaling via IRE-1-associated programs (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 8-10) |
| Overall interpretation | Developmentally dominant, highly abundant, folding-centered BiP paralog with additional specialized roles in immunity and proteostasis buffering (urban2025functionallydiversifiedbip pages 29-33, couillault2012auprindependentinfectionspecific pages 7-8, urban2025functionallydiversifiedbip pages 21-25) | More inducible, adulthood- and stress-oriented BiP paralog specialized for adaptive UPRER signaling, intestinal homeostasis, and autophagy/ER-phagy responses (urban2025functionallydiversifiedbip pages 18-21, urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedcaenorhabditis pages 8-10) |
Table: This table compares the two C. elegans BiP orthologs across localization, expression, stress regulation, pathway involvement, tissue roles, and aging phenotypes. It is useful for distinguishing the more developmentally abundant, folding-centered HSP-3 from the more stress-inducible, signaling-linked HSP-4.
The following table provides a pathway-level summary of HSP-3 involvement:
| Pathway/Process | Role of HSP-3 | Key Interactors | Evidence Type (genetic/biochemical/transcriptomic) | Key Reference |
|---|---|---|---|---|
| ER protein folding / quality control | Canonical ER-resident HSP70/BiP chaperone that supports de novo folding and refolding of misfolded secretory-pathway proteins; more developmentally abundant and folding-centered than HSP-4 (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 8-10) | HSP-4, ER client proteins, ER proteostasis machinery (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 1-2) | Genetic, expression/localization, functional inference from family/domain conservation (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedbip pages 14-18) | Urban et al., 2025 bioRxiv / Nature Communications (urban2025functionallydiversifiedbip pages 29-33, urban2025functionallydiversifiedcaenorhabditis pages 1-2) |
| Unfolded Protein Response (IRE-1/XBP-1, PEK-1, ATF-6) | UPR target and regulator: basal and stress-induced expression depends strongly on IRE-1/XBP-1; hsp-3 loss activates compensatory UPR programs and engages all three ER stress sensors in specific proteotoxic contexts (urban2025functionallydiversifiedbip pages 18-21, shen2001complementarysignalingpathways pages 7-8, pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 14-16) | IRE-1, XBP-1, PEK-1, ATF-6, ATF-4, eIF2A, HSP-4 (urban2025functionallydiversifiedbip pages 18-21, pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 14-16) | Genetic, reporter-based, transcriptomic (urban2025functionallydiversifiedbip pages 18-21, shen2001complementarysignalingpathways pages 7-8, pelt2025lossoffic1mediated pages 1-2) | Shen et al., 2001 Cell; Van Pelt & Truttmann, 2025 PLOS Genetics (shen2001complementarysignalingpathways pages 7-8, pelt2025lossoffic1mediated pages 1-2) |
| FIC-1 / AMPylation regulation | Direct substrate of the Fic AMPylase FIC-1; AMPylated at Thr176 in the nucleotide-binding domain, implying post-translational tuning of HSP-3/BiP state and ER proteostasis capacity (truttmann2016thecaenorhabditiselegans pages 13-14, truttmann2016thecaenorhabditiselegans pages 11-13, chatterjee2021ficandnonfic pages 14-15) | FIC-1, ATP, Thr176 residue in HSP-3 NBD (truttmann2016thecaenorhabditiselegans pages 13-14, truttmann2016thecaenorhabditiselegans pages 11-13) | Biochemical, mass spectrometry, genetic (truttmann2016thecaenorhabditiselegans pages 13-14, truttmann2016thecaenorhabditiselegans pages 11-13) | Truttmann et al., 2016 PLOS Genetics; Chatterjee & Truttmann, 2021 Open Biology (truttmann2016thecaenorhabditiselegans pages 13-14, chatterjee2021ficandnonfic pages 14-15) |
| Innate immunity / antifungal signaling | Has a UPR-independent, infection-specific role in epidermal antimicrobial peptide induction; acts downstream of NIPI-3 and upstream of or parallel to TPA-1 to promote nlp-29 expression after fungal infection (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) | NIPI-3, TPA-1, nlp-29, HSP-4 (partial compensation context) (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) | Genetic, epistasis, proteomic candidate follow-up (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) | Couillault et al., 2012 Virulence (couillault2012auprindependentinfectionspecific pages 7-8, couillault2012auprindependentinfectionspecific pages 5-7) |
| Temperature-dependent germline sex determination | BiP pool encoded by hsp-3/hsp-4 functions as a temperature sensor; reduced available BiP under warmer conditions transduces ER folding demand into a signal promoting sperm fate upstream of TRA-2 (shi2024identificationofbip pages 9-10) | HSP-4, TRA-2, ER folding load / ERAD-linked machinery (shi2024identificationofbip pages 9-10) | Genetic, physiological, mechanistic inference (shi2024identificationofbip pages 9-10) | Shi et al., 2024 EMBO Journal (shi2024identificationofbip pages 9-10) |
| Polyglutamine / proteotoxic stress | Loss of hsp-3 worsens ER homeostasis and causes developmental arrest in polyQ-expressing worms; fic-1 deletion rescues via UPRER activation and induction of cytosolic HSP70s, especially F44E5.4 (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4, pelt2025lossoffic1mediated pages 10-14) | FIC-1, IRE-1, ATF-6, PEK-1, F44E5.4, F44E5.5, small HSPs, glutathione transferases (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 14-16, pelt2025lossoffic1mediated pages 10-14) | Genetic, transcriptomic, lifespan/developmental assays (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4, pelt2025lossoffic1mediated pages 10-14) | Van Pelt & Truttmann, 2025 PLOS Genetics (pelt2025lossoffic1mediated pages 1-2, pelt2025lossoffic1mediated pages 2-4) |
| Aging and lifespan regulation | Required for normal lifespan with strong developmental-stage specificity; HSP-3 abundance is high during larval stages, loss shortens lifespan, and overexpression can extend lifespan; tissue-specific effects include germline dependence (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) | HSP-4, germline, intestine, daf-2/reduced insulin signaling context (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8) | Genetic, temporal/tissue-specific knockdown, expression profiling (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 5-8, urban2025functionallydiversifiedbip pages 21-25) | Urban et al., 2025 Nature Communications / bioRxiv (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 21-25) |
| ER-phagy / ER homeostasis remodeling | Participates in BiP-dependent ER proteostasis programs linked to ER-phagy, but appears less directly tied than HSP-4 to autophagy induction; contributes to maintaining ER quality during aging and stress (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 33-36, urban2025functionallydiversifiedcaenorhabditis pages 8-10) | HSP-4, IRE-1, ER-phagy factors such as Sec-62/C18E9.2-linked pathways (urban2025functionallydiversifiedbip pages 33-36, urban2025functionallydiversifiedcaenorhabditis pages 8-10) | Genetic, functional, transcriptomic inference (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedcaenorhabditis pages 8-10) | Urban et al., 2025 Nature Communications / bioRxiv (urban2025functionallydiversifiedcaenorhabditis pages 1-2, urban2025functionallydiversifiedbip pages 33-36) |
| Neuron-glia communication | HSP-3 is highly expressed in neurons and is implicated, together with HSP-4, in ER-stress-linked neuron-glia signaling during aging; evidence is currently stronger for a shared BiP/HSP-mediated IRE1-XBP1 axis than for an HSP-3-specific mechanism (urban2025functionallydiversifiedbip pages 18-21) | HSP-4, neurons, glia, IRE1-XBP1 pathway (urban2025functionallydiversifiedbip pages 18-21) | Expression/localization, emerging functional evidence (urban2025functionallydiversifiedbip pages 18-21) | Urban et al., 2025 bioRxiv; related 2024 preprint literature noted in search context (urban2025functionallydiversifiedbip pages 18-21) |
Table: This table summarizes the major signaling pathways and biological processes involving C. elegans HSP-3, highlighting its role, interacting factors, evidence types, and key references. It is useful for quickly distinguishing HSP-3’s core ER chaperone function from its more specialized roles in immunity, proteotoxic stress, aging, and signaling.
HSP-3 shares greater than 80% sequence similarity with human BiP/GRP78 (truttmann2016thecaenorhabditiselegans pages 13-14). Its domain architecture — comprising an N-terminal ATPase/nucleotide-binding domain, a substrate-binding domain, and a C-terminal lid domain — is conserved across the HSP70 superfamily. The Thr176 AMPylation site lies within a strictly conserved sequence motif (AVVTVPAYFND) shared among BiP homologs, though the modification site itself is distinct from mammalian BiP AMPylation sites, reflecting species-specific evolution of regulatory mechanisms (truttmann2016thecaenorhabditiselegans pages 13-14, camara2022hypemediatedampylationas pages 37-41). The KDEL ER-retention motif on HSP-3 (versus HDEL on HSP-4) represents a further point of functional divergence that may influence ER retention efficiency and cycling between the ER and Golgi (couillault2012auprindependentinfectionspecific pages 7-8, shen2001complementarysignalingpathways pages 2-3).
HSP-3 is a multifunctional ER-resident HSP70/BiP chaperone in C. elegans whose primary role is the ATP-dependent folding and refolding of client proteins within the ER lumen. It is distinguished from its paralog HSP-4 by higher basal expression, developmental stage-specificity (peaking at L3/L4), sensitivity to FIC-1-mediated AMPylation, and a unique UPR-independent role in epidermal innate immunity. HSP-3 participates in all three branches of the UPR^ER and is essential for developmental protein quality control, lifespan regulation, and stress resistance. Recent discoveries have further revealed its involvement in temperature-dependent germline sex determination and proteotoxic stress responses, making it a central node in C. elegans ER biology with implications for understanding conserved mechanisms of protein homeostasis, aging, and disease.
References
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