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Le Thomas A, Ferri E, Marsters S, et al. Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α. Nat Commun. 2021;12(1):7310doi: 10.1038/s41467-021-27597-7.
Le Thomas, A., Ferri, E., Marsters, S., Harnoss, J. M., Lawrence, D. A., Zuazo-Gaztelu, I., Modrusan, Z., Chan, S., Solon, M., Chalouni, C., Li, W., Koeppen, H., Rudolph, J., Wang, W., Wu, T. D., Walter, P., & Ashkenazi, A. (2021). Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α. Nature communications, 12(1), 7310. https://doi.org/10.1038/s41467-021-27597-7
Le Thomas, Adrien, et al. "Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α." Nature communications vol. 12,1 (2021): 7310. doi: https://doi.org/10.1038/s41467-021-27597-7
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 Commun. 2021 Dec 15;12(1):7310. doi: 10.1038/s41467-021-27597-7. PMID: 34911951; PMCID: PMC8674358.
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Nat Commun. 2021 Dec 15;12(1):7310. doi: 10.1038/s41467-021-27597-7.

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

Nature communications

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 Koeppen, Joachim Rudolph, Weiru Wang, Thomas D Wu, Peter Walter, Avi Ashkenazi

Affiliations

  1. Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
  2. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
  3. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
  4. Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
  5. Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
  6. Howard Hughes Medical Institute, University of California, San Francisco, CA, 94143, USA.
  7. University of California, San Francisco, CA, 94143, USA.
  8. Department of Oncology Bioinformatics Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. [email protected].
  9. Howard Hughes Medical Institute, University of California, San Francisco, CA, 94143, USA. [email protected].
  10. University of California, San Francisco, CA, 94143, USA. [email protected].
  11. Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. [email protected].

PMID: 34911951 PMCID: PMC8674358 DOI: 10.1038/s41467-021-27597-7

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.

© 2021. The Author(s).

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