Skip to main content
eScholarship
Open Access Publications from the University of California

UCSF

UC San Francisco Previously Published Works bannerUCSF

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.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View