title: The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling.
abstract: The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense. Here, we report that inositol-requiring-1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by binding a portion of cholera toxin as it co-opts the ER to cause disease. Other known UPR transducers, including the IRE1α-dependent transcription factor XBP1, are dispensable for this signaling. The inflammatory response depends instead on the RNase activity of IRE1α to degrade endogenous mRNA, a process termed regulated IRE1α-dependent decay (RIDD) of mRNA. The mRNA fragments produced engage retinoic-acid inducible gene 1 (RIG-I), a cytosolic sensor of RNA viruses, to activate NF-κB and interferon pathways. We propose IRE1α provides for a generalized mechanism of innate immune surveillance originating within the ER lumen.
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jin A
authors.initials: JA
authors.lastname: Cho
authors.affiliation: Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Platzer
authors.affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: Benedict C S
authors.initials: BCS
authors.lastname: Cross
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Gardner
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: De Luca
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Phi
authors.initials: P
authors.lastname: Luong
authors.affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.affiliation: Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA; Howard Hughes Medical Institute.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Kagan
authors.affiliation: Department of Medicine, Division of GI Cell Biology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: wayne.lencer@childrens.harvard.edu.
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
mesh_terms: D002460:Cell Line; D002772:Cholera Toxin / Q000276:immunology* / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology* / Q000378:metabolism; D004722:Endoribonucleases / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: D011971:Receptors, Immunologic; D002772:Cholera Toxin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases