The RIDD activity of C. elegans IRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival.

Xbp1 splicing and regulated IRE1-dependent RNA decay (RIDD) are two RNase activities of the ER stress sensor IRE1. While Xbp1 splicing has important roles in stress responses and animal physiology, the physiological role(s) of RIDD remain enigmatic. Genetic evidence in C. elegans connects 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 of C. elegans IRE1 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-7 was degraded in human cells by both human and worm IRE1 RNAse activity with same efficiency and specificity as Blos1, confirming daf-7 as RIDD substrate. Surprisingly, daf-7 degradation in vivo was triggered by concentrations of ER stressor tunicamycin too low for xbp-1 splicing. Decrease in DAF-7 normally signals food limitation and harsh environment, triggering adaptive changes to promote population survival. Because C. elegans is a bacteriovore, and tunicamycin, like other common ER stressors, is an antibiotic secreted by Streptomyces spp., we asked whether daf-7 degradation by RIDD could signal pending food deprivation. Indeed, pre-emptive tunicamycin exposure increased survival of C. elegans populations under food limiting/high temperature stress, and this protection was abrogated by overexpression of DAF-7. Thus, C. elegans uses 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.