title: Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.
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(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lupfer
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Paras K
authors.initials: PK
authors.lastname: Anand
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: Gonghua
authors.initials: G
authors.lastname: Huang
authors.forename: Maggie
authors.initials: M
authors.lastname: Green
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D000071189:Autophagy-Related Protein-1 Homolog; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D007110:Immunity, Active / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism*; D029521:Alphainfluenzavirus / Q000276:immunology*; D020382:Interleukin-18 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D063306:Mitophagy; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D037521:Virulence Factors; D013481:Superoxides; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C112444:Ulk1 protein, mouse; D020170:Caspase 1