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Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α.

  • Author(s): Le Thomas, Adrien;
  • Ferri, Elena;
  • Marsters, Scot;
  • Harnoss, Jonathan M;
  • Lawrence, David A;
  • Zuazo-Gaztelu, Iratxe;
  • Modrusan, Zora;
  • Chan, Sara;
  • Solon, Margaret;
  • Chalouni, Cécile;
  • Li, Weihan;
  • Koeppen, Hartmut;
  • Rudolph, Joachim;
  • Wang, Weiru;
  • Wu, Thomas D;
  • Walter, Peter;
  • Ashkenazi, Avi
  • et al.

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 IRE1α-controlled 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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