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CHOP and IRE1α-XBP1/JNK signaling promote Newcastle Disease Virus induced apoptosis and benefit virus proliferation

Yanrong Li, Ying Liao, Qiaona Niu, Feng Gu, Yingjie Sun, Chunchun Meng, Lei Tan, Cuiping Song, Xusheng Qiu, Chan Ding
doi: https://doi.org/10.1101/300129
Yanrong Li
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Ying Liao
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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  • For correspondence: liaoying@shvri.ac.cn shoveldeen@shvri.ac.cn
Qiaona Niu
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Feng Gu
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Yingjie Sun
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Chunchun Meng
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Lei Tan
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Cuiping Song
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Xusheng Qiu
1Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241. P. R. China
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Chan Ding
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
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  • For correspondence: liaoying@shvri.ac.cn shoveldeen@shvri.ac.cn
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ABSTRACT

Newcastle disease virus (NDV) causes severe infectious disease in poultry, and selectively kills tumor cells by inducing apoptosis. In this report, we revealed the mechanisms underlying NDV-induced apoptosis via investigation of endoplasmic reticulum (ER) stress-related unfolded protein response (UPR) in HeLa cells. We found that NDV infection induced the expression of pro-apoptotic transcription factor CHOP via PKR-eIF2α pathway. Knock down and exogenous expression studies showed that CHOP promoted cell apoptosis by down-regulation of anti-apoptotic protein BCL-2 and MCL-1, promotion of pro-apoptotic JNK and p38 signaling, and suppression of pro-survival AKT signaling. Meanwhile, CHOP facilitated NDV proliferation. Furthermore, virus infection activated IRE1α, another ER stress sensor, thereby promoting the mRNA splicing of XBP1 and resulting in the translation of transcription factor XBP1s. XBP1s entered into cell nucleus, promoted the expression of ER chaperones and components of ER associated degradation (ERAD). Exogenous expression of XBP1s helped IBV proliferation, and silence of XBP1s reduced virus proliferation. Meanwhile, exogenous expression and knock down studies demonstrated that IRE1α activated pro-apoptotic JNK signaling, promoted apoptosis and inflammation. In conclusion, our current study demonstrates that the induction of CHOP and activation of IRE1α-XBP1/JNK signaling cascades promote apoptosis and benefit NDV proliferation.

IMPORTANCE It is well known that NDV kills host animal and tumor cells by inducing cell apoptosis. Although several studies investigate the apoptotic phenomena in NDV-infected tumor cells, the molecular mechanisms underlying this oncolytic virus induced apoptosis is not well understood yet. In this study, we focus on characterization of the ER stress responses in NDV-infected tumor cells, and find that virus induces apoptosis by up-regulation or activation of several unfolded protein responses (UPR) related transcription factors and signaling: such as ATF4, CHOP and XBP1s, and pro-apoptotic kinases (IRE1α, JNK, p38). Moreover, activation of these transcription factors and signaling cascades helps virus proliferation. Our study dissects the UPR induced apoptosis in NDV-infected tumor cells, and provides the evidence that UPR favors NDV proliferation.

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Posted April 12, 2018.
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CHOP and IRE1α-XBP1/JNK signaling promote Newcastle Disease Virus induced apoptosis and benefit virus proliferation
Yanrong Li, Ying Liao, Qiaona Niu, Feng Gu, Yingjie Sun, Chunchun Meng, Lei Tan, Cuiping Song, Xusheng Qiu, Chan Ding
bioRxiv 300129; doi: https://doi.org/10.1101/300129
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CHOP and IRE1α-XBP1/JNK signaling promote Newcastle Disease Virus induced apoptosis and benefit virus proliferation
Yanrong Li, Ying Liao, Qiaona Niu, Feng Gu, Yingjie Sun, Chunchun Meng, Lei Tan, Cuiping Song, Xusheng Qiu, Chan Ding
bioRxiv 300129; doi: https://doi.org/10.1101/300129

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