NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

• Published in: The Journal of clinical investigation Vol. 120; no. 5; pp. 1645 - 1662
• Main Authors: Watanabe, Tomohiro, Asano, Naoki, Fichtner-Feigl, Stefan, Gorelick, Peter L, Tsuji, Yoshihisa, Matsumoto, Yuko, Chiba, Tsutomu, Fuss, Ivan J, Kitani, Atsushi, Strober, Warren
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2010
• Subjects: Animals; Biomedical research; Chemokines; Chemokines - metabolism; Cytokines; Female; Helicobacter Infections - metabolism; Helicobacter pylori; Helicobacter pylori - metabolism; Humans; Infections; Interferon Type I - metabolism; Interferon-Stimulated Gene Factor 3 - metabolism; Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism; Kinases; Ligands; Male; Mice; Mice, Inbred C57BL; Nod1 Signaling Adaptor Protein - metabolism; Peptides; Peptides - chemistry; Protein Binding; Signal Transduction; Th1 Cells - cytology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci39481

Nucleotide-binding oligomerization domain 1 (NOD1) 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 NOD1, 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 IkappaB kinase epsilon (IKKepsilon) 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.