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

Author

Listed:
  • Adrien Le Thomas

    (Genentech, Inc.)

  • Elena Ferri

    (Genentech, Inc.
    Genentech, Inc.)

  • Scot Marsters

    (Genentech, Inc.)

  • Jonathan M. Harnoss

    (Genentech, Inc.)

  • David A. Lawrence

    (Genentech, Inc.)

  • Iratxe Zuazo-Gaztelu

    (Genentech, Inc.)

  • Zora Modrusan

    (Proteomics and Lipidomics, Genentech, Inc.)

  • Sara Chan

    (Genentech, Inc.)

  • Margaret Solon

    (Genentech, Inc.)

  • Cécile Chalouni

    (Genentech, Inc.)

  • Weihan Li

    (Howard Hughes Medical Institute, University of California
    University of California)

  • Hartmut Koeppen

    (Genentech, Inc.)

  • Joachim Rudolph

    (Genentech, Inc.)

  • Weiru Wang

    (Genentech, Inc.)

  • Thomas D. Wu

    (Inc.)

  • Peter Walter

    (Howard Hughes Medical Institute, University of California
    University of California)

  • Avi Ashkenazi

    (Genentech, Inc.)

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 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.

Suggested Citation

  • Adrien Le Thomas & Elena Ferri & Scot Marsters & Jonathan M. Harnoss & David A. Lawrence & Iratxe Zuazo-Gaztelu & Zora Modrusan & Sara Chan & Margaret Solon & Cécile Chalouni & Weihan Li & Hartmut Koe, 2021. "Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27597-7
    DOI: 10.1038/s41467-021-27597-7
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    Cited by:

    1. Ekaterina Borisova & Andrew G. Newman & Marta Couce Iglesias & Rike Dannenberg & Theres Schaub & Bo Qin & Alexandra Rusanova & Marisa Brockmann & Janina Koch & Marieatou Daniels & Paul Turko & Olaf Ja, 2024. "Protein translation rate determines neocortical neuron fate," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    2. Fátima Cairrão & Cristiana C. Santos & Adrien Thomas & Scot Marsters & Avi Ashkenazi & Pedro M. Domingos, 2022. "Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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