The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling

Cell Host Microbe. 2013 May 15;13(5):558-569. doi: 10.1016/j.chom.2013.03.011.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Cell Line
  • Cholera Toxin / immunology*
  • Cholera Toxin / metabolism*
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / immunology*
  • DEAD-box RNA Helicases / metabolism
  • Endoribonucleases / immunology*
  • Endoribonucleases / metabolism*
  • Humans
  • Immunity, Innate*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*

Substances

  • Cholera Toxin
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases