| 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 (pqac-00000001, pqac-00000008) | BiP/GRP78-family ER-resident HSP70 chaperone encoded by **hsp-4**; paralog of hsp-3 and canonical UPR reporter target in many studies (pqac-00000001, pqac-00000008) |
| ER retention motif | **KDEL** ER-retention motif reported for HSP-3 (pqac-00000003, pqac-00000009) | **HDEL** ER-retention motif reported for HSP-4 (pqac-00000009) |
| 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 (pqac-00000004, pqac-00000009) | Lower basal expression than HSP-3 during development; minimal in larval stages relative to HSP-3 (pqac-00000004, pqac-00000018) |
| Stress inducibility | Induced by ER stress, but more modestly than hsp-4; DTT induced hsp-3 ~2-fold in early UPR work (pqac-00000009) | Strongly stress inducible; DTT induced hsp-4 ~9-fold, making it the more classic inducible UPR target (pqac-00000009) |
| 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 (pqac-00000000, pqac-00000021) | Shares ER folding function but appears more specialized for **ER stress mitigation, signaling integration, and adaptive proteostasis programs** rather than primarily direct refolding (pqac-00000007, pqac-00000021) |
| Tissue-enriched expression | Broadly expressed; in early adulthood HSP-3 is especially abundant in **intestine and neurons** (pqac-00000016) | Also induced in intestine and neurons under ER stress; later-life expression becomes more prominent than during larval stages (pqac-00000007, pqac-00000018) |
| Intestine-specific roles | Intestine-specific loss of hsp-3 did **not** significantly alter lifespan in the 2025 study (pqac-00000017) | Intestinal hsp-4 loss shortened lifespan and caused severe defects including early death/matricide, indicating a stronger intestinal homeostatic requirement (pqac-00000019, pqac-00000020) |
| Germline-specific roles | Germline-specific ablation shortens lifespan, showing a germline requirement for organismal aging control (pqac-00000017, pqac-00000020) | Germline loss also shortens lifespan, in some analyses more severely than hsp-3 loss (pqac-00000019, pqac-00000020) |
| 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 (pqac-00000016, pqac-00000017) | 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 (pqac-00000007) |
| 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 (pqac-00000004, pqac-00000018) | Low during larval development, rises strongly in adulthood, with peak abundance later than HSP-3 (around day 10 adults in the 2025 study) (pqac-00000018) |
| Role in basal UPR regulation | Basal expression requires **IRE-1**; during ER stress, upregulation depends strongly on **IRE-1/XBP-1** (pqac-00000007, pqac-00000008) | 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 (pqac-00000007) |
| 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** (pqac-00000022, pqac-00000025) | Loss of hsp-4 more strongly resembles overt UPRER activation and is more tightly integrated with the broader three-sensor UPR network (pqac-00000007) |
| 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 (pqac-00000002, pqac-00000019, pqac-00000020) | Loss also shortens lifespan, but HSP-4 is more critical during **adulthood** and in intestine-centered longevity control (pqac-00000019, pqac-00000020) |
| 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 (pqac-00000018, pqac-00000019) | Also participates in DR/IIS longevity regulation, but with distinct tissue/time requirements from HSP-3 (pqac-00000018, pqac-00000019) |
| FIC-1 AMPylation | **Direct FIC-1 target**; AMPylated at **Thr176** in the nucleotide-binding domain, indicating post-translational regulation of HSP-3 activity/state (pqac-00000010, pqac-00000011, pqac-00000013) | No comparable FIC-1 AMPylation evidence was identified in the cited studies; HSP-4 was not highlighted as the FIC-1-modified BiP paralog (pqac-00000012, pqac-00000013) |
| 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 (pqac-00000003, pqac-00000006) | 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 (pqac-00000003, pqac-00000006) |
| 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 (pqac-00000022, pqac-00000023, pqac-00000026) | hsp-4 depletion also perturbs ER homeostasis, but transcriptomic and signaling consequences are distinct and complementary to hsp-3 loss (pqac-00000022) |
| 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 (pqac-00000001, pqac-00000005) | 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 (pqac-00000001, pqac-00000021) |
| Overall interpretation | Developmentally dominant, highly abundant, folding-centered BiP paralog with additional specialized roles in immunity and proteostasis buffering (pqac-00000000, pqac-00000003, pqac-00000020) | More inducible, adulthood- and stress-oriented BiP paralog specialized for adaptive UPRER signaling, intestinal homeostasis, and autophagy/ER-phagy responses (pqac-00000007, pqac-00000019, pqac-00000021) |


*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.*