Herpes simplex virus protein kinase US3 activates and functionally overlaps protein kinase A to block apoptosis
Herpes simplex virus protein kinase US3 activates and functionally overlaps protein kinase A to block apoptosis
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DOI：
10.1073/pnas.0403160101
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发表时间：
2004-06-22
影响因子：
11.1
通讯作者：
Roizman, B
中科院分区：
文献类型：
--
作者：
Benetti, L;Roizman, B
单纯疱疹病毒1编码至少四种基因，其功能包括阻断由外源性试剂（例如，山梨糖醇、Fas配体和BAD蛋白）或无复制能力的突变体（例如，缺乏α 4基因的两个拷贝的D120突变体）。U（S）3是这四个基因之一，编码丝氨酸-苏氨酸激酶，已证明其阻断由促凋亡细胞蛋白或d120突变体诱导的凋亡。由U（S）3磷酸化的丝氨酸-苏氨酸的氨基酸背景与cAMP依赖性蛋白激酶PKA的氨基酸背景相似。我们报道了（i）在转导的细胞中或在用WT病毒感染的细胞中，被U（S）3磷酸化的蛋白质的模式与PKA靶向的磷蛋白的模式重叠，（h）PKA的活化阻断了由d120突变体或由BAD蛋白诱导的凋亡，而与U（S）3无关，（三）U（S）3蛋白激酶磷酸化含有PKA靶向的丝氨酸或苏氨酸的肽，包括PKA的调节型II α亚基中存在的丝氨酸或苏氨酸，和（iv）在WT病毒感染的细胞中，调节II型α亚基以U（S）3依赖性方式磷酸化。我们的结论是，U（S）3蛋白激酶的抗凋亡活性的一个主要决定因素是PKA底物的磷酸化的一种或两种酶。
Herpes simplex virus 1 encodes at least four genes whose functions include blocking apoptosis induced by exogenous agents (e.g., sorbitol, Fas ligand, and BAD protein) or replication-incompetent mutants (e.g., the d120 mutant lacking both copies of the alpha4 gene). U(S)3, one of these four genes, encodes a serine-threonine kinase that has been demonstrated to block apoptosis induced by proapoptotic cellular proteins or by the d120 mutant. The amino acid context of serine-threonine phosphorylated by U(S)3 is similar to that of the cAMP-dependent protein kinase PKA. We report that (i) the pattern of proteins phosphorylated by U(S)3 in transduced cells or in cells infected with WT virus overlaps that of phosphoproteins targeted by PKA, (h) activation of PKA blocks apoptosis induced by d120 mutant or by BAD protein independently of U(S)3, (iii) U(S)3 protein kinase phosphorylates peptides containing the serine or threonine targeted by PKA including that present in the regulatory type IIalpha subunit of PKA, and (iv) in WT virus-infected cells the regulatory type IIalpha subunit is phosphorylated in a U(S)3-dependent manner. We conclude that a major determinant of the antiapoptotic activity of the U(S)3 protein kinase is the phosphorylation of PKA substrates by either or both enzymes.