IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27597-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27597-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27597-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27597-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.