Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma(1)34.5 protein.
The gamma(1)34.5 protein of herpes simplex virus (HSV) plays a crucial role in virus infection. Although the double-stranded RNA-dependent protein kinase (PKR) is activated during HSV infection, the gamma(1)34.5 protein inhibits the activity of PKR by mediating dephosphorylation of the translation initiation factor eIF-2alpha. Here we show that HSV infection also induces phosphorylation of an endoplasmic reticulum (ER) resident kinase PERK, a hallmark of ER stress response. The virus-induced phosphorylation of PERK is blocked by cycloheximide but not by phosphonoacetic acid, suggesting that the accumulation of viral proteins in the ER is essential. Notably, the maximal phosphorylation of PERK is delayed in PKR+/+ cells compared to that seen in PKR-/- cells. Further analysis indicates that hyperphosphorylation of eIF-2alpha caused by HSV is greater in PKR+/+ cells than in PKR-/- cells. However, expression of the gamma(1)34.5 protein suppresses the ER stress response caused by virus, dithiothreitol, and thapsigargin as measured by global protein synthesis. Interestingly, the expression of GADD34 stimulated by HSV infection parallels the status of eIF-2alpha phosphorylation. Together, these observations suggest that regulation of eIF-2alpha phosphorylation by the gamma(1)34.5 protein is an efficient way to antagonize the inhibitory activity of PKR as well as PERK during productive infection.
Cheng
Guofeng
G
Department of Microbiology and Immunology (M/C 790), College of Medicine, The University of Illinois at Chicago, 835 South Wolcott Ave., Chicago, IL 60612, USA.
Feng
Zongdi
Z
He
Bin
B
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D014764:Viral Proteins / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D009363:Neoplasm Proteins; D054645:Protein Phosphatase 1; D014764:Viral Proteins; D019892:eIF-2 Kinase; C066469:gamma 34.5 protein, Human herpesvirus 1; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse