Nature communicationsDec 12, 2025

Different versions of a key protein in Caenorhabditis elegans affect growth, reproduction, stress resistance, aging, and cell cleanup

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Diversified BiP-like ER chaperones in C. elegans help tune growth, reproduction, stress resilience, aging, and autophagy.

Evidence

This mechanistic C. elegans study, with supporting human cell data, compared HSP-3 and HSP-4 functions across tissues, age, stress responses, longevity pathways, and protein aggregation stress.

Caveat

The findings are mainly from worm and cell models, so the proposed BiP-IRE-1-Sec-62 autophagy mechanism is not yet shown as a human physiological or clinical effect.

Simplified

Cellular systems governing protein folding depend on functional redundancy and diversification to maintain proteostasis. Here, using Caenorhabditis elegans, we show two homologous ER-resident HSP70 chaperones, HSP-3 and HSP-4, have overlapping and distinct roles in ER proteostasis and organismal physiology. Their expression and function vary by tissue, age, and stress, impacting ER stress resistance, reproduction, body size, and lifespan. We also find HSP-3 and HSP-4 uniquely regulate dietary restriction and reduced insulin signaling-mediated longevity in C. elegans. Notably, knockdown of hsp-4, but not hsp-3, induces autophagy and enhances tolerance to protein aggregation stress; this process requires the ortholog of receptor Sec-62 (C18E9.2) and IRE-1. Finally, human cell data suggests that the dissociation of chaperone Binding Immunoglobulin Protein (BiP) from IRE-1 during times of ER stress promotes autophagy by enhancing the interaction of IRE-1 and Sec-62. These findings reveal how ER chaperone diversification maximizes stress resilience and suggest a BiP-dependent regulation of autophagy.

Key numbers

240

Gene Upregulation

Distinct genes upregulated upon HSP-4 compared to control.

Gene Downregulation

Distinct genes downregulated upon HSP-3 compared to control.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Different versions of a key protein in Caenorhabditis elegans affect growth, reproduction, stress resistance, aging, and cell cleanup

Abstract

Key numbers

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief