Regulated Ire1-dependent decay of messenger RNAs in mammalian cells

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.

[1]  D. Pincus,et al.  Messenger RNA targeting to endoplasmic reticulum stress signalling sites. , 2009, Nature.

[2]  Chao Zhang,et al.  The unfolded protein response signals through high-order assembly of Ire1 , 2009, Nature.

[3]  D. Ron,et al.  IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. , 2008, Cell metabolism.

[4]  John Bechill,et al.  Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression , 2008, Journal of Virology.

[5]  Kathryn L. Lipson,et al.  The Role of IRE1α in the Degradation of Insulin mRNA in Pancreatic β-Cells , 2008, PloS one.

[6]  F. R. Papa,et al.  A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress. , 2008, Biochemical and biophysical research communications.

[7]  Chao Zhang,et al.  IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response , 2007, Science.

[8]  T. Iwawaki,et al.  Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1. , 2007, Biochemical and biophysical research communications.

[9]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[10]  A. Protopopov,et al.  The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis , 2007, Cancer cell.

[11]  B. Panning,et al.  XIST RNA exhibits nuclear retention and exhibits reduced association with the export factor TAP/NXF1 , 2007, Chromosoma.

[12]  J. Taunton,et al.  Substrate-Specific Translocational Attenuation during ER Stress Defines a Pre-Emptive Quality Control Pathway , 2006, Cell.

[13]  Jonathan S Weissman,et al.  Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response , 2006, Science.

[14]  M. Niwa,et al.  Intrinsic capacities of molecular sensors of the unfolded protein response to sense alternate forms of endoplasmic reticulum stress. , 2006, Molecular biology of the cell.

[15]  J. Alwine,et al.  Human Cytomegalovirus Infection Activates and Regulates the Unfolded Protein Response , 2005, Journal of Virology.

[16]  D. Scheuner,et al.  The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. , 2005, The Journal of clinical investigation.

[17]  E. C. Dell'Angelica,et al.  Identification of Snapin and Three Novel Proteins (BLOS1, BLOS2, and BLOS3/Reduced Pigmentation) as Subunits of Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1)* , 2004, Journal of Biological Chemistry.

[18]  M. Lehrman,et al.  Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts. , 2004, Biochemical and biophysical research communications.

[19]  A. Siddiqui,et al.  Hepatitis C Virus Suppresses the IRE1-XBP1 Pathway of the Unfolded Protein Response* , 2004, Journal of Biological Chemistry.

[20]  Chao Zhang,et al.  Bypassing a Kinase Activity with an ATP-Competitive Drug , 2003, Science.

[21]  L. Glimcher,et al.  XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response , 2003, Molecular and Cellular Biology.

[22]  K. Rajewsky,et al.  Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 , 2003, Nature Immunology.

[23]  J. W. Brewer,et al.  Activation of an Unfolded Protein Response during Differentiation of Antibody-secreting B Cells* , 2002, The Journal of Biological Chemistry.

[24]  Peichuan Zhang,et al.  The PERK Eukaryotic Initiation Factor 2α Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas , 2002, Molecular and Cellular Biology.

[25]  Hiderou Yoshida,et al.  IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. , 2002, Genes & development.

[26]  D. Ron,et al.  Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. , 2001, Molecular cell.

[27]  T. Iwawaki,et al.  Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress , 2001, Nature Cell Biology.

[28]  R. Kaufman,et al.  The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. , 2000, Genes & development.

[29]  Peter G. Schultz,et al.  A chemical switch for inhibitor-sensitive alleles of any protein kinase , 2000, Nature.

[30]  D. Ron,et al.  Perk is essential for translational regulation and cell survival during the unfolded protein response. , 2000, Molecular cell.