Journal article
Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection
C Lupfer, PG Thomas, PK Anand, P Vogel, S Milasta, J Martinez, G Huang, M Green, M Kundu, H Chi, RJ Xavier, DR Green, M Lamkanfi, CA Dinarello, PC Doherty, TD Kanneganti
Nature Immunology | Published : 2013
DOI: 10.1038/ni.2563
Abstract
NOD2 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 infection with influenza A virus. Ripk2 -/- cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1 -/- cel..
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Awarded by European Commission
Funding Acknowledgements
We thank members of the Veterinary Pathology Core lab at St. Jude for their work in processing of hematoxylin and eosin-stained and immunohistochemistry slides, members of the Cell and Tissue Imaging Core facility for their help in preparing and imaging transmission electron microscopy samples, and A. Coyle, E. Grant, J. Bertin (Millennium Pharmaceuticals), T. Mak (University of Toronto) and R. Flavell (Yale University) for providing mutant mice. M. L. is supported by grants from the EU Framework Program 7 (Marie-Curie grant 256432), European Research Council (grant 281600) and the Fund for Scientific Research Flanders (G030212N, 1.2.201.10.N.00 and 1.5.122.11.N.00). This work was supported by US National Institutes of Health grants (AR056296, AI101935 and CA163507) and the American Lebanese Syrian Associated Charities to T.-D.K.