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Regulation of de novo translation of host cells by manipulation of PERK/PKR and GADD34-PP1 activity during Newcastle disease virus infection
- Source :
- Journal of General Virology. 97:867-879
- Publication Year :
- 2016
- Publisher :
- Microbiology Society, 2016.
-
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.
- Subjects :
- 0301 basic medicine
viruses
Eukaryotic Initiation Factor-2
Newcastle disease virus
Biology
environment and public health
Cell Line
eIF-2 Kinase
03 medical and health sciences
Eukaryotic translation
Protein Phosphatase 1
Virology
Protein biosynthesis
Animals
Humans
Phosphorylation
Protein Kinase Inhibitors
RNA, Double-Stranded
EIF-2 kinase
030102 biochemistry & molecular biology
ATF4
Translation (biology)
Fibroblasts
Activating Transcription Factor 4
Protein kinase R
Receptors, Neuropeptide Y
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Gene Expression Regulation
Protein Biosynthesis
Host-Pathogen Interactions
Proteolysis
biology.protein
RNA, Viral
Signal transduction
Chickens
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 14652099 and 00221317
- Volume :
- 97
- Database :
- OpenAIRE
- Journal :
- Journal of General Virology
- Accession number :
- edsair.doi.dedup.....b93b752226f5d4613573de66dabf080f