Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response

Julie Hollien, and Jonathan S. Weissman^*

Abstract: The unfolded protein response (UPR) allows the endoplasmic reticulum (ER) to recover from the accumulation of misfolded proteins, in part by increasing its folding capacity. Inositol-requiring enzyme–1 (IRE1) promotes this remodeling by detecting misfolded ER proteins and activating a transcription factor, X-box–binding protein 1, through endonucleolytic cleavage of its messenger RNA (mRNA). Here, we report that IRE1 independently mediates the rapid degradation of a specific subset of mRNAs, based both on their localization to the ER membrane and on the amino acid sequence they encode. This response is well suited to complement other UPR mechanisms because it could selectively halt production of proteins that challenge the ER and clear the translocation and folding machinery for the subsequent remodeling process.

Department of Cellular and Molecular Pharmacology, University of California San Francisco, Howard Hughes Medical Institute, and the California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco, CA 94143, USA.

^* To whom correspondence should be addressed. E-mail: weissman{at}cmp.ucsf.edu

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