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

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.