RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus

被引：292

作者：

Nogusa, Shoko ^{[1
]}

Thapa, Roshan J. ^{[1
]}

Dillon, Christopher P. ^{[2
]}

Liedmann, Swantje ^{[2
]}

Oguin, Thomas H., III ^{[2
]}

Ingram, Justin P. ^{[1
]}

Rodriguez, Diego A. ^{[2
]}

Kosoff, Rachelle ^{[1
]}

Sharma, Shalini ^{[2
]}

Sturm, Oliver ^{[2
]}

Verbist, Katherine ^{[2
]}

Gough, Peter J. ^{[3
]}

Bertin, John ^{[3
]}

Hartmann, Boris M. ^{[4
]}

Sealfon, Stuart C. ^{[4
]}

Kaiser, William J. ^{[5
]}

Mocarski, Edward S. ^{[5
]}

Lopez, Carolina B. ^{[6
]}

Thomas, Paul G. ^{[2
]}

Oberst, Andrew ^{[7
]}

Green, Douglas R. ^{[2
]}

Balachandran, Siddharth ^{[1
]}

机构：

[1] Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[2] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] GlaxoSmithKline, Pattern Recognit Receptor Discovery Performance U, Immunoinflammat Therapeut Area, Collegeville, PA 19426 USA

[4] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA

[5] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA

[6] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA

[7] Univ Washington, Dept Microbiol & Immunol, Seattle, WA 98109 USA

来源：

CELL HOST & MICROBE | 2016年 / 20卷 / 01期

关键词：

CELL-DEATH; PROGRAMMED NECROSIS; NLRP3; INFLAMMASOME; KINASE INHIBITORS; SIGNALING PATHWAY; IN-VIVO; INFECTION; MICE; RESPONSES; TARGET;

D O I：

10.1016/j.chom.2016.05.011

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Influenza A virus (IAV) is a lytic virus in primary cultures of many cell types and in vivo. We report that the kinase RIPK3 is essential for IAV-induced lysis of mammalian fibroblasts and lung epithelial cells. Replicating IAV drives assembly of a RIPK3-containing complex that includes the kinase RIPK1, the pseudokinase MLKL, and the adaptor protein FADD, and forms independently of signaling by RNA-sensing innate immune receptors (RLRs, TLRs, PKR), or the cytokines type I interferons and TNF-alpha. Downstream of RIPK3, IAV activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis, with the former reliant on RIPK3 kinase activity and neither on RIPK1 activity. Mice deficient in RIPK3 or doubly deficient in MLKL and FADD, but not MLKL alone, are more susceptible to IAV than their wild-type counterparts, revealing an important role for RIPK3-mediated apoptosis in antiviral immunity. Collectively, these results outline RIPK3-activated cytolytic mechanisms essential for controlling respiratory IAV infection.

引用

页码：13 / 24

页数：12

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