RETRACTED: The Unfolded Protein Response Element IRE1α Senses Bacterial Proteins Invading the ER to Activate RIG-I and Innate Immune Signaling
Authors: Heidi De Luca
Benedict C S Cross
David Ron
Laurie H Glimcher
Edda Fiebiger
Ann-Hwee Lee
Jin A Cho
Phi Luong
Jonathan C Kagan
Peter Walter
Heather P Harding
Barbara Platzer
Brooke M Gardner
Wayne I Lencer
Journal: Cell Host & Microbe (2013)
Discipline: MICROBIOLOGY
Keywords: Plasma membrane; Membrane-bound organelles; Golgi; Endoplasmic reticulum; Pattern-recognition molecules
Affiliations: 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; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA., University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK., Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA., Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA., Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA; Howard Hughes Medical Institute., 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., 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: .

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. 

Retracted: Yes

PubPeer comments:
 https: www.cell.com cell-host-microbe fulltext S1931-3128(18)30134-3 u201c(Cell Host Microbe 13, 558u2013569; May 15, 2013) In 2013, we reported in Cell Host Microbe that when the AB5 subunit cholera toxin (CTx) enters the ER of host cells, the toxinu2019s enzymatic A subunit can activate the ER stress sensor IRE1u03b1 to induce an inflammatory response by regulated IRE1u03b1-dependent decay of mRNA (RIDD) and subsequent activation of the cytoplasmic viral RNA sensor RIG-I. Although we can reproduce the findings that CTx and its unfolding and enzymatically inactive mutants can activate IRE1u03b1 (as evidenced by XBP-1 splicing), and that all toxins can induce an inflammatory response (as evidenced by transcription of IL-6 and IL-8), we cannot reproduce the qRT-PCR experiments that show that the IL-6 inflammatory response depends on IRE1u03b1 activation, and we cannot locate the original qPCR datasets to verify the original results. Therefore, we cannot confirm or stand behind the data published in Figures 3G, 4A, and 4C and the conclusion that IRE1u03b1 is the sole mediator for cholera toxin-induced inflammatory signals. This diminishes the evidence for mechanism of action by IRE1u03b1-induced activation of RIG-I. We wish to correct the literature by retracting the entire paper. We sincerely apologize for this occurrence and any confusion it might have caused.u201d ,