title: Regulation of de novo translation of host cells by manipulation of PERK/PKR and GADD34-PP1 activity during Newcastle disease virus infection.
abstract: Viral infections result in cellular stress responses, which can trigger protein translation shutoff via phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Newcastle disease virus (NDV) causes severe disease in poultry and selectively kills human tumour cells. In this report, we determined that infection of HeLa human cervical cancer cells and DF-1 chicken fibroblast cells with NDV maintained protein at early infection times, 0-12 h post-infection (p.i.), and gradually inhibited global protein translation at late infection times, 12-24 h p.i. Mechanistic studies showed that translation inhibition at late infection times was accompanied by phosphorylation of eIF2α, a checkpoint of translation initiation. Meanwhile, the eIF2α kinase, PKR, was upregulated and activated by phosphorylation and another eIF2α kinase, PERK, was phosphorylated and cleaved into two fragments. Pharmacological inhibition experiments revealed that only PKR activity was required for eIF2α phosphorylation, suggesting that recognition of viral dsRNA by PKR was responsible for translation shutoff. High levels of phospho-eIF2α led to preferential translation of the transcription factor ATF4 and an increase in GADD34 expression. Functionally, GADD34, in conjunction with PP1, dephosphorylated eIF2a and restored protein translation, benefiting virus protein synthesis. However, PP1 was degraded at late infection times, functionally counteracting the upregulation of GADD34. Taken together, our data support that NDV-induced translation shutoff at late infection times was attributed to sustaining phosphorylation of eIF2α, which is mediated by continual activation of PKR and degradation of PP1.
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Ying
authors: Y
authors: Liao
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Feng
authors: F
authors: Gu
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Xiang
authors: X
authors: Mao
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Qiaona
authors: Q
authors: Niu
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Huaxia
authors: H
authors: Wang
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Yingjie
authors: Y
authors: Sun
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Cuiping
authors: C
authors: Song
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Xusheng
authors: X
authors: Qiu
authors: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Lei
authors: L
authors: Tan
authors: Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, JiangSu 225009, PRChina.|Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Ziyue Road 518, Shanghai 200241, PRChina.
authors: Chan
authors: C
authors: Ding
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002645:Chickens; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D009522:Newcastle disease virus / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D015852:Eukaryotic Initiation Factor-2; D047428:Protein Kinase Inhibitors; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D017476:Receptors, Neuropeptide Y; D051701:Activating Transcription Factor 4; C109491:neuropeptide Y4 receptor; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1