Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection

被引：328

作者：

Lupfer, Christopher ^{[1
]}

Thomas, Paul G. ^{[1
]}

Anand, Paras K. ^{[1
]}

Vogel, Peter ^{[2
]}

Milasta, Sandra ^{[1
]}

Martinez, Jennifer ^{[1
]}

Huang, Gonghua ^{[1
]}

Green, Maggie ^{[1
]}

Kundu, Mondira ^{[3
]}

Chi, Hongbo ^{[1
]}

Xavier, Ramnik J. ^{[4
,5
,6
,7
]}

Green, Douglas R. ^{[1
]}

Lamkanfi, Mohamed ^{[8
,9
]}

Dinarello, Charles A. ^{[10
]}

Doherty, Peter C. ^{[1
,11
]}

Kanneganti, Thirumala-Devi ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Vet Pathol Core, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[4] Harvard Univ, Sch Med, Gastrointestinal Unit, Boston, MA USA

[5] Harvard Univ, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA USA

[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[7] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA

[8] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium

[9] Univ Ghent VIB, Dept Med Prot Res, B-9052 Ghent, Belgium

[10] Univ Colorado Denver, Dept Med, Aurora, CO USA

[11] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia

来源：

NATURE IMMUNOLOGY | 2013年 / 14卷 / 05期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

IFN-GAMMA PRODUCTION; 1918; INFLUENZA; LISTERIA-MONOCYTOGENES; DENDRITIC CELLS; IMMUNE-RESPONSE; AUTOPHAGY; INNATE; NOD2; CRYOPYRIN/NALP3; NEUTRALIZATION;

D O I：

10.1038/ni.2563

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-kappa B 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.

引用

页码：480 / +

页数：11

共 49 条

[1] The NLRP3 Inflammasome Mediates In Vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA [J].

Allen, Irving C. ;

Scull, Margaret A. ;

Moore, Chris B. ;

Holl, Eda K. ;

McElvania-TeKippe, Erin ;

Taxman, Debra J. ;

Guthrie, Elizabeth H. ;

Pickles, Raymond J. ;

Ting, Jenny P. -Y. .

IMMUNITY, 2009, 30 (04) :556-565

[2] TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation [J].

Anand, Paras K. ;

Tait, Stephen W. G. ;

Lamkanfi, Mohamed ;

Amer, Amal O. ;

Nunez, Gabriel ;

Pages, Gilles ;

Pouyssegur, Jacques ;

McGargill, Maureen A. ;

Green, Douglas R. ;

Kanneganti, Thirumala-Devi .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (50) :42981-42991

[3]

BLACK RA, 1989, J BIOL CHEM, V264, P5323

[4] NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation [J].

Cooney, Rachel ;

Baker, John ;

Brain, Oliver ;

Danis, Benedicte ;

Pichulik, Tica ;

Allan, Philip ;

Ferguson, David J. P. ;

Campbell, Barry J. ;

Jewell, Derek ;

Simmons, Alison .

NATURE MEDICINE, 2010, 16 (01) :90-U128

[5] Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia [J].

de Jong, Menno D. ;

Simmons, Cameron P. ;

Thanh, Tran Tan ;

Hien, Vo Minh ;

Smith, Gavin J. D. ;

Chau, Tran Nguyen Bich ;

Hoang, Dang Minh ;

Chau, Nguyen Van Vinh ;

Khanh, Truong Huu ;

Dong, Vo Cong ;

Qui, Phan Tu ;

Van Cam, Bach ;

Ha, Do Quang ;

Guan, Yi ;

Peiris, J. S. Malik ;

Chinh, Nguyen Tran ;

Hien, Tran Tinh ;

Farrar, Jeremy .

NATURE MEDICINE, 2006, 12 (10) :1203-1207

[6] Nucleotide oligomerization domain-2 interacts with 2′-5′-oligoadenylate synthetase type 2 and enhances RNase-L function in THP-1 cells [J].

Dugan, Jae W. ;

Albor, Amador ;

David, Larry ;

Fowlkes, Jonathan ;

Blackledge, Marc T. ;

Martin, Tammy M. ;

Planck, Stephen R. ;

Rosenzweig, Holly L. ;

Rosenbaum, James T. ;

Davey, Michael P. .

MOLECULAR IMMUNOLOGY, 2009, 47 (2-3) :560-566

[7] The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations [J].

Geisler, Sven ;

Holmstroem, Kira M. ;

Treis, Angela ;

Skujat, Diana ;

Weber, Stephanie S. ;

Fiesel, Fabienne C. ;

Kahle, Philipp J. ;

Springer, Wolfdieter .

AUTOPHAGY, 2010, 6 (07) :871-878

[8] Involvement of toll-like receptor 3 in the immune response of lung evithelial cells to double-stranded RNA and influenza A virus [J].

Guillot, L ;

Le Goffic, R ;

Bloch, S ;

Escriou, N ;

Akira, S ;

Chignard, M ;

Si-Tahar, M .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (07) :5571-5580

[9] TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses [J].

Heer, Alex K. ;

Shamshiev, Abdijapar ;

Donda, Alena ;

Uematsu, Satoshi ;

Akira, Shizuo ;

Kopf, Manfred ;

Marsland, Benjamin J. .

JOURNAL OF IMMUNOLOGY, 2007, 178 (04) :2182-2191

[10] Eight-plasmid system for rapid generation of influenza virus vaccines [J].

Hoffmann, E ;

Krauss, S ;

Perez, D ;

Webby, R ;

Webster, RG .

VACCINE, 2002, 20 (25-26) :3165-3170

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