title: Regulated Ire1-dependent decay of messenger RNAs in mammalian cells.
abstract: 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.
authors: Department of Biology, University of Utah, Salt Lake City, UT 84112, USA. hollien@biology.utah.edu
authors: Julie
authors: J
authors: Hollien
authors: Jonathan H
authors: JH
authors: Lin
authors: Han
authors: H
authors: Li
authors: Nicole
authors: N
authors: Stevens
authors: Peter
authors: P
authors: Walter
authors: Jonathan S
authors: JS
authors: Weissman
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases