Getting RIDD of RNA: IRE1 in cell fate regulation

• XBP1 splicing and RIDD activities are differentially regulated functions of the UPR transducer IRE1.
• RIDD is a conserved ancestral mechanism regulating proteostasis in different eukaryotic phyla.
• RIDD has a basal activity that is required to maintain ER homeostasis.
• XBP1 splicing and RIDD produce opposite effects on cell fate in cells subjected to ER stress.

Inositol-requiring enzyme 1 (IRE1) is the most conserved transducer of the unfolded protein response (UPR), a homeostatic response that preserves proteostasis. Intriguingly, via its endoribonuclease activity, IRE1 produces either adaptive or death signals. This occurs through both unconventional splicing of XBP1 mRNA and regulated IRE1-dependent decay of mRNA (RIDD). Whereas XBP1 mRNA splicing is cytoprotective in response to endoplasmic reticulum (ER) stress, RIDD has revealed many unexpected features. For instance, RIDD cleaves RNA at an XBP1-like consensus site but with an activity divergent from XBP1 mRNA splicing and can either preserve ER homeostasis or induce cell death. Here we review recent findings on RIDD and propose a model of how IRE1 RNase activity might control cell fate decisions.