Lupfer, ChristopherThomas, Paul G.Anand, Paras K.Vogel, PeterMilasta, SandraMartinez, JenniferHuang, GonghuaGreen, MaggieKundu, MondiraChi, HongboXavier, RamnikGreen, Douglas R.Lamkanfi, MohamedDinarello, Charles A.Doherty, Peter C.Kanneganti, Thirumala-Devi2014-03-112013Lupfer, C., P. G. Thomas, P. K. Anand, P. Vogel, S. Milasta, J. Martinez, G. Huang, et al. 2013. “Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.” Nature immunology 14 (5): 480-488. doi:10.1038/ni.2563. http://dx.doi.org/10.1038/ni.2563.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879094NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2−/− and Ripk2−/− mice are hypersusceptible to influenza A virus infection. Ripk2−/− cells displayed defective mitophagy leading to enhanced mitochondrial superoxide production and accumulation of damaged mitochondria resulting in increased NLRP3 inflammasome activation and IL-18 production. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1−/− cells displayed enhanced mitochondrial superoxide production and caspase-1 activation. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating NLRP3 inflammasome activation and IL-18 production via ULK1-dependent mitophagy.en-USRIPK2NLRCaspase-1inflammasomeInfluenzaIL-18autophagymitophagyJournal Article2014-03-1110.1038/ni.2563