<i>Caenorhabditis elegans</i> inositol hexaphosphate pathways couple to RNA interference and pathogen defense.

Abstract

RNA interference (RNAi) is an evolutionarily conserved pathway that defends against viral infections in diverse organisms. <i>Caenorhabditis elegans</i> mutations that enhance RNAi have revealed pathways that may regulate antiviral defense. A genetic screen for <i>C. elegans</i> mutations that fail to up-regulate a defense response reporter transgene detected mutations that enhance RNAi to silence this reporter gene in the inositol polyphosphate multikinase <i>impk-1</i>, the synMuv B gene <i>lin-15B,</i> and the pathogen defense response gene <i>pals-22</i>. Using other assays for enhanced RNAi, we found that the <i>impk-1</i> alleles and an <i>ippk-1</i> gene inactivation of a later step in inositol hexaphosphate (IP₆) synthesis, and the <i>lin-15B</i> and <i>pals-22</i> alleles enhance RNAi. IP₆ has been known for decades to bind and stabilize human adenosine deaminase that acts on RNA (ADAR) as well as the paralog tRNA editing ADAT. We show that the <i>C. elegans</i> IP₆ pathway is also required for mRNA and tRNA editing. Thus, a deficiency in two axes of RNA editing enhances the already potent <i>C. elegans</i> RNAi antiviral defense, suggesting adenosine to inosine RNA editing may normally moderate this siRNA antiviral defense pathway. The <i>C. elegans</i> IP₆-deficient mutants are synthetic lethal with a set of enhanced RNAi mutants that act in the polyploid hypodermis to regulate collagen secretion and signaling from that tissue, implicating IP₆ signaling especially in this tissue. This enhanced antiviral RNAi response uses the <i>C. elegans</i> RIG-I-like receptor DRH-1 to activate the unfolded protein response (UPR). The production of primary siRNAs, rather than secondary siRNAs, contributes to this activation of the UPR through XBP-1 signaling. The <i>gon-14</i> and <i>pal-17</i> mutants that also emerged from this screen act in the mitochondrial defense pathway rather than by enhancing RNAi.