Herpes Simplex Virus 1 (HSV-1) ICP22 protein directly interacts with cyclin-dependent kinase (CDK)9 to inhibit RNA polymerase II transcription elongation.
Herpes Simplex Virus 1 (HSV-1) ICP22 protein directly interacts with cyclin-dependent kinase (CDK)9 to inhibit RNA polymerase II transcription elongation.
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DOI：
10.1371/journal.pone.0107654
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Murphy S
中科院分区：
文献类型：
--
作者：
Zaborowska J;Baumli S;Laitem C;O'Reilly D;Thomas PH;O'Hare P;Murphy S
单纯疱疹病毒1型(HSV-1)编码的ICP22蛋白在病毒感染中起重要作用，并影响宿主细胞基因的表达。已知ICP22可以降低Tyr1Ser2Pro3Thr4Ser5Pro6Ser7七肽重复序列的丝氨酸(Ser)2磷酸化水平，该重复序列包含RNA聚合酶(PolII)大亚基的羧基末端结构域(CTD)。因此，ICP22被认为与正转录延伸因子b(P-TEFb)polII CTD Ser2激酶的活性相关并抑制其活性。我们在这里证明了ICP22导致在HeLa细胞中异位表达后参与蛋白质编码基因转录的PolII的CTD Ser2磷酸化丧失，并且重组ICP22与重组P-TEFb的CDK9亚基相互作用。ICP22在体外也能与PolII相互作用。ICP22的193-256位残基足以与CDK9相互作用，并抑制PolII CTD Ser2的磷酸化，但不与PolII相互作用。这些结果表明，ICP22的不同区域与CDK9或PolII相互作用，ICP22与CDK9直接相互作用，从而抑制宿主细胞基因的表达。
The Herpes Simplex Virus 1 (HSV-1)-encoded ICP22 protein plays an important role in viral infection and affects expression of host cell genes. ICP22 is known to reduce the global level of serine (Ser)2 phosphorylation of the Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 heptapeptide repeats comprising the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase (pol) II. Accordingly, ICP22 is thought to associate with and inhibit the activity of the positive-transcription elongation factor b (P-TEFb) pol II CTD Ser2 kinase. We show here that ICP22 causes loss of CTD Ser2 phosphorylation from pol II engaged in transcription of protein-coding genes following ectopic expression in HeLa cells and that recombinant ICP22 interacts with the CDK9 subunit of recombinant P-TEFb. ICP22 also interacts with pol II in vitro. Residues 193 to 256 of ICP22 are sufficient for interaction with CDK9 and inhibition of pol II CTD Ser2 phosphorylation but do not interact with pol II. These results indicate that discrete regions of ICP22 interact with either CDK9 or pol II and that ICP22 interacts directly with CDK9 to inhibit expression of host cell genes.
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