Deubiquitinase USP-14 regulates intestinal distension-induced immunity via Wnt/β-catenin signaling in C. elegans

Pathogen infections disrupt multiple host cellular processes, and hosts have consequently evolved mechanisms to detect these perturbations and initiate appropriate immune responses. In Caenorhabditis elegans, gut distension caused by bacterial colonization is known to activate innate immunity, yet the molecular mechanisms linking intestinal distension to immune activation remain poorly understood. Here, we perform a forward genetic screen to identify suppressors of intestinal distension-induced immune activation in C. elegans. This screen identifies a loss-of-function mutation in the gene encoding the deubiquitinase (DUB) USP-14 as a potent suppressor of immune activation triggered by gut distension. We show that usp-14 knockout mutants exhibit increased sensitivity to the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Global transcriptomic profiling further demonstrates that USP-14 modulates innate immune responses induced by intestinal distension. Epistasis analyses establish that USP-14 functions through the Wnt/β-catenin signaling pathway to regulate these immune responses. Together, our findings reveal a previously unrecognized role for the conserved DUB USP-14 in host immunity, providing a foundation for future studies investigating how USP-14 modulates immune signaling.