Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 5, Pages 1645-1662Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39481
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Funding
- Ministry of Education, Science and Culture, Japan
- Japan Society for the Promotion of Science [21590532]
- Takeda Science Foundation
- Ichiro Kanehara Memorial Foundation for Medical Research
- Astellas Foundation for Research on Metabolic Disorders
- Yakult Bioscience Foundation
- Sumitomo Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [21590532] Funding Source: KAKEN
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Nucleotide-binding oligomerization domain 1 (NOD 1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD 1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and I kappa B kinase epsilon (IKK epsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.
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