The RIDD activity ofC. elegansIRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival

Abstract

AbstractXbp1splicing and regulated IRE1-dependent RNA decay (RIDD) are two RNase activities of the ER stress sensor IRE1. WhileXbp1splicing has important roles in stress responses and animal physiology, the physiological role(s) of RIDD remain enigmatic. Genetic evidence inC. elegansconnects XBP1-independent IRE1 activity to organismal stress adaptation, but whether this is via RIDD, and what are the targets is yet unknown. We show that cytosolic kinase/RNase domain ofC. elegansIRE1 is indeed capable of RIDD in human cells, and that sensory neurons use RIDD to signal environmental stress, by degrading mRNA of TGFβ-like growth factor DAF-7.daf-7was degraded in human cells by both human and worm IRE1 RNAse activity with same efficiency and specificity asBlos1,confirmingdaf-7as RIDD substrate. Surprisingly,daf-7degradationin vivowas triggered by concentrations of ER stressor tunicamycin too low forxbp-1splicing. Decrease in DAF-7 normally signals food limitation and harsh environment, triggering adaptive changes to promote population survival. BecauseC. elegansis a bacteriovore, and tunicamycin, like other common ER stressors, is an antibiotic secreted byStreptomyces spp., we asked whetherdaf-7degradation by RIDD could signal pending food deprivation. Indeed, pre-emptive tunicamycin exposure increased survival ofC. eleganspopulations under food limiting/high temperature stress, and this protection was abrogated by overexpression of DAF-7. Thus,C. elegansuses stress-inducing metabolites in its environment as danger signals, and employs IRE1’s RIDD activity to modulate the neuroendocrine signaling for survival of upcoming environmental challenge.