TY - JOUR
T1 - RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus
AU - Nogusa, Shoko
AU - Thapa, Roshan J.
AU - Dillon, Christopher P.
AU - Liedmann, Swantje
AU - Oguin, Thomas H.
AU - Ingram, Justin P.
AU - Rodriguez, Diego A.
AU - Kosoff, Rachelle
AU - Sharma, Shalini
AU - Sturm, Oliver
AU - Verbist, Katherine
AU - Gough, Peter J.
AU - Bertin, John
AU - Hartmann, Boris M.
AU - Sealfon, Stuart C.
AU - Kaiser, William J.
AU - Mocarski, Edward S.
AU - López, Carolina B.
AU - Thomas, Paul G.
AU - Oberst, Andrew
AU - Green, Douglas R.
AU - Balachandran, Siddharth
N1 - Funding Information:
We are grateful to Vishva Dixit, Adolfo Garcia-Sastre, Scott Hensley, Ganes Sen, and Luis Sigal for viruses, cells, and mice. This work was supported by NIAID contract HHSN272201400006C (St. Jude Center of Excellence for Influenza Research and Surveillance) to P.G.T., NIH grant AI109472 to C.B.L., NIH grants AI44828 and CA169291 to D.R.G., and NIH grants CA168621, CA190542, and AI113469 to S.B. Additional funds were provided by the F.M. Kirby Foundation, and via NIH Cancer Center Support Grant P30CA006927 to S.B. P.J.G. and J.B. are employees of GlaxoSmithKline.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/13
Y1 - 2016/7/13
N2 - 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-α. 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.
AB - 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-α. 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.
UR - http://www.scopus.com/inward/record.url?scp=84978648026&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2016.05.011
DO - 10.1016/j.chom.2016.05.011
M3 - Article
C2 - 27321907
AN - SCOPUS:84978648026
SN - 1931-3128
VL - 20
SP - 13
EP - 24
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -