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Abstract
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.
Highlights
The endoplasmic reticulum (ER) plays an important role in regulating protein synthesis/processing, lipid synthesis, and calcium homeostasis[1]
At 20 h.p.i., increased number of TUNEL positive cells was observed in human cervical cancer cell line (HeLa) (Fig. 1a), as well as in Chicken embryo fibroblasts (CEFs), DF-1, Cal[27], HN13, A549, H1299, Huh[7], and HepG2 cells (Fig. S1A); only few TUNEL positive cells were observed in 293T cells (Fig. S1A)
Immunoblotting showed that in HeLa, Cal[27], HN13, A549, and H1299 cells, both major biochemical markers of apoptosis, caspase-3 and PARP, were cleaved into smaller fragments in an infection time-dependent manner; in Huh[7] and HepG2 cells, weak cleavage of PARP appeared at 24 h.p.i.; no cleavage of both biochemical markers was observed in 293T cells (Fig. 1c and Fig. S1C)
Summary
The endoplasmic reticulum (ER) plays an important role in regulating protein synthesis/processing, lipid synthesis, and calcium homeostasis[1]. Many viral proteins are synthesized by ER-associated ribosome and transported into the ER lumen for proper folding or posttranslational modification. This leads to an Official journal of the Cell Death Differentiation Association. ATF6-N and subsequently translocated to the nucleus as an active transcription factor, triggering the transcription of protein chaperones and components of ER-associated degradation (ERAD)[9,10,11]. After dissociating from Bip, IRE1α undergoes homooligomerization and autophosphorylation, obtaining both kinase and endoribonuclease activity[13]. This endoribonuclease leads to unconventional enzymatic splicing of XBP1u mRNA into XBP1s by removing the 26-nucleotide intron. IRE1α degrades ER-associated mRNAs to attenuate protein load in the ER lumen[16]
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