IRE1α Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2

TLDR

The unfolded protein response (UPR) adjusts ER folding capacity, with IRE1α as a key RNase that splices XBP1 mRNA, but sustained IRE1α activity during irreparable ER stress triggers cell death and activates Caspase‑2 as an early apoptotic switch. The study aims to clarify how ER stress detection leads to Caspase‑2 activation. The authors show that IRE1α activates Caspase‑2 via a non‑coding RNA–mediated pathway. IRE1α RNase activity degrades specific microRNAs that repress Caspase‑2 translation, causing a rapid rise in Caspase‑2 protein and initiating its activation. Upton et al., p.

Abstract

To Die For The unfolded protein response (UPR) adjusts the protein folding capacity of the endoplasmic reticulum (ER) to match demand. UPR signaling requires IRE1α, an ER transmembrane kinase-endoribonuclease (RNase) that becomes activated by unfolded protein accumulation within the ER and excises a segment in XBP1 messenger RNA (mRNA) to initiate production of the homeostatic transcription factor XBP1s. However, if ER stress is irremediable, sustained IRE1α RNase activity triggers cell death. Severe ER stress activates the protease Caspase-2 as an early apoptotic switch upstream of mitochondria. However, the molecular events leading from the detection of ER stress to Caspase-2 activation are unclear. Upton et al. (p. 818 , published online 4 October) now report that IRE1α is the ER stress sensor that activates Caspase-2, and does so through a mechanism involving non-coding RNAs. Under irremediable ER stress, IRE1α's RNase triggers the rapid decay of select microRNAs that normally repress translation of Caspase-2 mRNA, rapidly increasing Caspase-2 levels as the first step in its activation.