| 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 (pqac-00000000, pqac-00000021) | HSP-4, ER client proteins, ER proteostasis machinery (pqac-00000000, pqac-00000001) | Genetic, expression/localization, functional inference from family/domain conservation (pqac-00000000, pqac-00000004) | Urban et al., 2025 bioRxiv / Nature Communications (pqac-00000000, pqac-00000001) |
| 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 (pqac-00000007, pqac-00000008, pqac-00000022, pqac-00000025) | IRE-1, XBP-1, PEK-1, ATF-6, ATF-4, eIF2A, HSP-4 (pqac-00000007, pqac-00000022, pqac-00000025) | Genetic, reporter-based, transcriptomic (pqac-00000007, pqac-00000008, pqac-00000022) | Shen et al., 2001 Cell; Van Pelt & Truttmann, 2025 PLOS Genetics (pqac-00000008, pqac-00000022) |
| 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 (pqac-00000010, pqac-00000011, pqac-00000013) | FIC-1, ATP, Thr176 residue in HSP-3 NBD (pqac-00000010, pqac-00000011) | Biochemical, mass spectrometry, genetic (pqac-00000010, pqac-00000011) | Truttmann et al., 2016 PLOS Genetics; Chatterjee & Truttmann, 2021 Open Biology (pqac-00000010, pqac-00000013) |
| 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 (pqac-00000003, pqac-00000006) | NIPI-3, TPA-1, nlp-29, HSP-4 (partial compensation context) (pqac-00000003, pqac-00000006) | Genetic, epistasis, proteomic candidate follow-up (pqac-00000003, pqac-00000006) | Couillault et al., 2012 Virulence (pqac-00000003, pqac-00000006) |
| 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 (pqac-00000015) | HSP-4, TRA-2, ER folding load / ERAD-linked machinery (pqac-00000015) | Genetic, physiological, mechanistic inference (pqac-00000015) | Shi et al., 2024 EMBO Journal (pqac-00000015) |
| 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 (pqac-00000022, pqac-00000023, pqac-00000026) | FIC-1, IRE-1, ATF-6, PEK-1, F44E5.4, F44E5.5, small HSPs, glutathione transferases (pqac-00000022, pqac-00000025, pqac-00000026) | Genetic, transcriptomic, lifespan/developmental assays (pqac-00000022, pqac-00000023, pqac-00000026) | Van Pelt & Truttmann, 2025 PLOS Genetics (pqac-00000022, pqac-00000023) |
| 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 (pqac-00000018, pqac-00000019, pqac-00000020) | HSP-4, germline, intestine, daf-2/reduced insulin signaling context (pqac-00000018, pqac-00000019) | Genetic, temporal/tissue-specific knockdown, expression profiling (pqac-00000018, pqac-00000019, pqac-00000020) | Urban et al., 2025 Nature Communications / bioRxiv (pqac-00000018, pqac-00000020) |
| 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 (pqac-00000001, pqac-00000005, pqac-00000021) | HSP-4, IRE-1, ER-phagy factors such as Sec-62/C18E9.2-linked pathways (pqac-00000005, pqac-00000021) | Genetic, functional, transcriptomic inference (pqac-00000001, pqac-00000021) | Urban et al., 2025 Nature Communications / bioRxiv (pqac-00000001, pqac-00000005) |
| 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 (pqac-00000016) | HSP-4, neurons, glia, IRE1-XBP1 pathway (pqac-00000016) | Expression/localization, emerging functional evidence (pqac-00000016) | Urban et al., 2025 bioRxiv; related 2024 preprint literature noted in search context (pqac-00000016) |


*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.*