Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, P. R. China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, P. R. China.
Cell Death Dis. 2019 Nov 26;10(12):891. doi: 10.1038/s41419-019-2128-6.
Newcastle disease virus (NDV) causes severe infectious disease in poultry and selectively kills tumor cells, by inducing apoptosis and cytokines secretion. In this report, we study the mechanisms underlying NDV-induced apoptosis by investigating the unfolded protein response (UPR). We found that NDV infection activated all three branches of the UPR signaling (PERK-eIF2α, ATF6, and IRE1α) and triggered apoptosis, in avian cells (DF-1 and CEF) and in various human cancer cell types (HeLa, Cal27, HN13, A549, H1299, Huh7, and HepG2). Interestingly, the suppression of either apoptosis or UPR led to impaired NDV proliferation. Meanwhile, the inhibition of UPR by 4-PBA protected cells from NDV-induced apoptosis. Further study revealed that activation of PERK-eIF2α induced the expression of transcription factor CHOP, which subsequently promoted apoptosis by downregulating BCL-2/MCL-1, promoting JNK signaling and suppressing AKT signaling. In parallel, IRE1α mediated the splicing of XBP1 mRNA and resulted in the translation and nuclear translocation of XBP1s, thereby promoting the transcription of ER chaperones and components of ER-associated degradation (ERAD). Furthermore, IRE1α promoted apoptosis and cytokines secretion via the activation of JNK signaling. Knock down and overexpression studies showed that CHOP, IRE1α, XBP1, and JNK supported efficient virus proliferation. Our study demonstrates that the induction of eIF2α-CHOP-BCL-2/JNK and IRE1α-XBP1/JNK signaling cascades promote apoptosis and cytokines secretion, and these signaling cascades support NDV proliferation.
新城疫病毒（NDV）可引起家禽的严重传染病，并通过诱导细胞凋亡和细胞因子分泌选择性杀死肿瘤细胞。在本报告中，我们通过研究未折叠蛋白反应（UPR）来研究 NDV 诱导细胞凋亡的机制。我们发现，NDV 感染激活了 UPR 信号传导的三条分支（PERK-eIF2α、ATF6 和 IRE1α），并引发了细胞凋亡，包括禽类细胞（DF-1 和 CEF）和多种人类癌细胞类型（HeLa、Cal27、HN13、A549、H1299、Huh7 和 HepG2）。有趣的是，抑制凋亡或 UPR 会导致 NDV 增殖受损。同时，4-PBA 抑制 UPR 可保护细胞免受 NDV 诱导的凋亡。进一步研究表明，PERK-eIF2α 的激活诱导了转录因子 CHOP 的表达，随后通过下调 BCL-2/MCL-1、促进 JNK 信号和抑制 AKT 信号来促进凋亡。同时，IRE1α 介导 XBP1 mRNA 的剪接，导致 XBP1s 的翻译和核转位，从而促进 ER 伴侣和 ER 相关降解（ERAD）成分的转录。此外，IRE1α 通过激活 JNK 信号促进凋亡和细胞因子分泌。敲低和过表达研究表明，CHOP、IRE1α、XBP1 和 JNK 支持病毒的有效增殖。我们的研究表明，eIF2α-CHOP-BCL-2/JNK 和 IRE1α-XBP1/JNK 信号级联的诱导促进了细胞凋亡和细胞因子分泌，这些信号级联支持 NDV 的增殖。
