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Regulated Ire1-dependent decay of messenger RNAs in mammalian cells

¹ Department of Biology, University of Utah, Salt Lake City, UT 84112
² Howard Hughes Medical Institute, ³ Department of Cellular and Molecular Pharmacology, and ⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158

Correspondence to Julie Hollien: hollien{at}biology.utah.edu

Maintenance of endoplasmic reticulum (ER) function is achieved in part through Ire1 (inositol-requiring enzyme 1), a transmembrane protein activated by protein misfolding in the ER. The cytoplasmic nuclease domain of Ire1 cleaves the messenger RNA (mRNA) encoding XBP-1 (X-box–binding protein 1), enabling splicing and production of this active transcription factor. We recently showed that Ire1 activation independently induces the rapid turnover of mRNAs encoding membrane and secreted proteins in Drosophila melanogaster cells through a pathway we call regulated Ire1-dependent decay (RIDD). In this study, we show that mouse fibroblasts expressing wild-type Ire1 but not an Ire1 variant lacking nuclease activity also degrade mRNAs in response to ER stress. Using a second variant of Ire1 that is activated by a small adenosine triphosphate analogue, we show that although XBP-1 splicing can be artificially induced in the absence of ER stress, RIDD appears to require both Ire1 activity and ER stress. Our data suggest that cells use a multitiered mechanism by which different conditions in the ER lead to distinct outputs from Ire1.

© 2009 Hollien et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Abbreviations used in this paper: BiP, immunoglobin-binding protein; FRT, ferritin-like protein recombination target; hIre1, human Ire1-; MEF, mouse embryonic fibroblast; qPCR, quantitative real-time PCR; RIDD, regulated Ire1-dependent decay; Tm, tunicamycin; UPR, unfolded protein response.

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