Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection
Thomas, Paul G.
Anand, Paras K.
Green, Douglas R.
Dinarello, Charles A.
Doherty, Peter C.
Kanneganti, Thirumala-DeviNote: Order does not necessarily reflect citation order of authors.
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CitationLupfer, 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.
AbstractNOD2 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.
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