RIP1 is a central signaling protein in regulation of TNF-α/TRAIL mediated apoptosis and necroptosis during Newcastle disease virus infection
Metrics: PDF 1047 views | HTML 971 views | ?
Ying Liao1,*, Hua-Xia Wang3,*, Xiang Mao1, Hongjie Fang3, Huang Wang1, Yanrong Li1, Yingjie Sun1, Chun Meng1, Lei Tan1, Cuiping Song1, Xusheng Qiu1 and Chan Ding1,2
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, P. R. China
2Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, P. R. China
3College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
*These authors have contributed equally as first author
Ying Liao, email: email@example.com
Chan Ding, email: firstname.lastname@example.org
Keywords: NDV, apoptosis, necroptosis, RIP1
Received: November 01, 2016 Accepted: April 11, 2017 Published: May 18, 2017
Newcastle disease virus (NDV) is an oncolytic virus which selectively replicates in tumor cells and exerts anti-tumor cytotoxic activity by promoting cell death. In this study, we focus on characterization of the underlying mechanisms of NDV-induced cell death in HeLa cells. We find that NDV Herts/33 strain triggers both extrinsic and intrinsic apoptosis at late infection times. The activation of NF-кB pathway and subsequent up-regulation of TNF-α/TRAIL initiates extrinsic apoptosis, leading to activation of caspase 8 and cleavage of Bid into tBid. tBid transmits the extrinsic apoptotic signals to mitochondria and mediates intrinsic apoptosis, which is hallmarked by cleavage of caspase 9. Moreover, RIP1 is cleaved into RIP1-N and RIP1-C at D324 by caspase 8, and this cleavage promotes apoptosis. Surprisingly, over expression of RIP1 reduces apoptosis and depletion of RIP1 promotes apoptosis, suggesting full length RIP1 is anti-apoptotic. Moreover, necroptosis hallmark protein MLKL is activated by phosphorylation at 12-24 h.p.i., and RIP1 regulates the level of phosphor-MLKL. Immunostaining shows that RIP1 aggregates to stress granules (SGs) at 8-24 h.p.i., and phosphor-MLKL is also recruited to SGs, instead of migrating to plasma membrane to exert its necrotic function. Immunoprecipitation study demonstrates that RIP1 bind to phosphor-MLKL, and depletion of RIP1 reduces the aggregation of MLKL to SGs, suggesting that RIP1 recruits MLKL to SGs. Altogether, NDV infection initiates extrinsic apoptosis via activation of NF-кB and secretion of TNF-α/TRAIL. Activation of caspase 8 by TNF-α/TRAIL and subsequent cleavage of Bid and RIP1 transmit the death signals to mitochondria. Meanwhile, virus subverts the host defensive necroptosis via recruiting phosphor-MLKL by RIP1 to SGs. Thus, RIP1 is a central signaling protein in regulation of apoptosis and necroptosis during NDV infection.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.