Vesicular heat-shock proteins orchestrate an epithelial-sheath unfolded-protein-response circuit that buffers sensory ageing in Caenorhabditis elegans
June 20
Many animal tissues are organised as primary epithelial cells ensheathed by specialised support cells, and signal exchange between these compartments is essential for morphogenesis and lifelong tissue integrity. Canonical epithelial–sheath communication relies on soluble ligands that engage surface receptors, yet how stressed epithelia alert their neighbours to impending damage remains poorly understood.
Here we delineate a non-canonical pathway whereby epithelial cells export heat-shock proteins (HSPs) in small extracellular vesicles (sEVs) that are selectively captured by sheath cells, initiating a protective transcriptional programme.
In the amphid epithelium of Caenorhabditis elegans, longitudinal imaging of photoconvertible HSP-16.2-Dendra2 revealed that early-senescent ciliated epithelial cells accelerate vesicular HSP export 4–6 h before detectable loss of dye-filling or chemotactic performance. Epithelial-specific disruption of sEV biogenesis (rab-27 or tsg-101 RNAi) abrogated HSP transfer, while sheath-specific endocytosis blockade (dyn-1^K44A) prevented uptake, confirming directionality. Proteomic profiling of purified epithelial sEVs identified a conserved IRM-lectin motif; genetic removal of the cognate sheath-cell lectin LEC-12 eliminated selective targeting and dispersed vesicle distribution to surrounding neurons.
Vesicular HSPs activated the IRE-1/XBP-1 branch of the unfolded protein response exclusively in sheath cells, as demonstrated by xbp-1p::GFP splicing reporters and abolished in ire-1(−) or xbp-1(−) mutants rescued only by sheath-specific cDNA expression. Downstream RNA-seq uncovered a five-gene chondroitin synthase module headed by sqv-5 whose CRISPR tagging confirmed up-regulation at both mRNA and protein levels. Acute sqv-5 knockdown negated periciliary matrix thickening (electron tomography) and accelerated ciliary degeneration, whereas sheath-cell over-expression of sqv-5 preserved ciliary length even when sEV export was blocked.
These data establish a quantitative, causative chain—epithelial stress → sEV-HSP release → sheath-cell UPR activation → chondroitin-dependent matrix remodelling—that equalises ageing rates among amphid epithelial cells. Although extrapolation to other taxa awaits testing, the motif is conserved in Drosophila nephrocytes and murine airway organoids, where ectopic delivery of C. elegans sEV-HSPs triggered homologous UPR and matrix genes. Our findings nominate extracellular HSP trafficking and sheath-cell proteostasis as tractable leverage points for prolonging sensory organ healthspan.