Journal
CELL HOST & MICROBE
Volume 13, Issue 5, Pages 558-569Publisher
CELL PRESS
DOI: 10.1016/j.chom.2013.03.011
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Categories
Funding
- NIH [DK48106, DK084424, DK090603]
- Harvard Digestive Diseases Center [P30 DK34854, DK083894]
- CCFA
- Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund
- Wellcome Trust Principal Research Fellowship [084812/Z/08/Z]
- [AI093589]
- [R01AI075037]
- [1K01DK093597-01A1]
- [R01DK082448]
- [R01DK089211]
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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-1 alpha (IRE1 alpha), 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 IRE1 alpha-dependent transcription factor XBP1, are dispensable for this signaling. The inflammatory response depends instead on the RNase activity of IRE1 alpha to degrade endogenous mRNA, a process termed regulated IRE1 alpha-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-kappa B and interferon pathways. We propose IRE1 alpha provides for a generalized mechanism of innate immune surveillance originating within the ER lumen.
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