Walter Lab

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    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
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Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

Le Thomas A, Ferri E, Marsters S, Harnoss JM, Lawrence DA, Zuazo-Gaztelu I, Modrusan Z, Chan S, Solon M, Chalouni C, Li W, Koeppen H, Rudolph J, Wang W, Wu TD, Walter P, Ashkenazi A. Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α. Nat Comms DOI: 10.1038/s41467-021-27597-7, 2021
( PMID : not available ) (PDF)

Abstract

Inositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1αcontrolled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.


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