The gamma(1)34.5 protein of herpes simplex virus I complexes with protein phosphatase 1 alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase

被引:654
作者
He, B
Gross, M
Roizman, B
机构
[1] UNIV CHICAGO, MARJORIE B KOVLER VIRAL ONCOL LABS, CHICAGO, IL 60637 USA
[2] UNIV CHICAGO, DEPT PATHOL, CHICAGO, IL 60637 USA
关键词
growth arrest and DNA damage gene 34;
D O I
10.1073/pnas.94.3.843
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In human cells infected with herpes simplex virus 1 the double-stranded RNA-dependent protein kinase (PKR) is activated but phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2) and total shutoff of protein synthesis is observed only in cells infected with gamma(1)z34.5(-) mutants. The carboxyl-terminal 64 aa of gamma(1)34.5 protein are homologous to the corresponding domain of MyD116, the murine growth arrest and DNA damage gene 34 (GADD34) protein and the two domains are functionally interchangeable in infected cells. This report shows that (i) the carboxyl terminus of MyD116 interacts with protein phosphatase 1 alpha in yeast, and both MyD116 and gamma(1)34.5 interact with protein phosphatase 1 alpha in vitro; (ii) protein synthesis in infected cells is strongly inhibited by okadaic acid, a phosphatase 1 inhibitor; and (iii) the alpha subunit in purified eIF-2 phosphorylated in vitro is specifically dephosphorylated by S10 fractions of wild-type infected cells at a rate 3000 times that of mock-infected cells, whereas the elF-2 alpha-P phosphatase activity of gamma(1)34.5(-) virus infected cells is lower than that of mock-infected cells. The eIF-2 alpha-P phosphatase activities are sensitive to inhibitor 2. In contrast to eIF-2 alpha-P phosphatase activity, extracts of mock-infected cells exhibit a 2-fold higher phosphatase activity on [P-32]phosphorylase than extracts of infected cells. These results indicate that in infected cells, gamma(1)34.5 interacts with and redirects phosphatase to dephosphorylate eIF-2 alpha to enable continued protein synthesis despite the presence of activated PKR. The GADD34 protein may have a similar function in eukaryotic cells. The proposed mechanism for maintenance of protein synthesis in the face of double-stranded RNA accumulation is different from that described for viruses examined to date.
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收藏
页码:843 / 848
页数:6
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