Antagonism of Protein Kinase R by Large DNA Viruses.
Antagonism of Protein Kinase R by Large DNA Viruses.
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大DNA病毒对蛋白激酶R的拮抗作用
DOI：
10.3390/pathogens11070790
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发表时间：
2022-07-12
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数十年的痘苗病毒 (VACV) 研究提供了丰富的见解和工具，这些见解和工具已被证明在分子病毒学和发病机制的广泛研究中具有无价的价值。病毒面临的挑战之一是宿主细胞的内在防御，例如蛋白激酶 R 通路，它会响应许多病毒复制过程中积累的 dsRNA 来关闭蛋白质合成。 PKR 的激活会导致真核起始因子 2 (eIF2α) 的 α 亚基磷酸化、抑制蛋白质合成并限制病毒复制。 VACV 编码两种特征明确的拮抗剂 E3L 和 K3L，它们可以阻断 PKR 途径，从而使病毒能够有效复制。使用删除了主要因子 E3L 的 VACV，能够初步鉴定由人类巨细胞病毒 (HCMV)（一种流行且具有医学重要性的病毒）编码的 PKR 拮抗剂。了解 E3L 和 K3L 功能的分子机制有助于剖析人类和非人类 CMV 编码的 PKR 拮抗剂的结构域、物种特异性和进化潜力。虽然仍然认识到 VACV 和 CMV 在分子病毒学和复制策略方面的实质性差异，但这篇综述说明了 VACV 如何为其他实验上不易处理的病毒的研究提供有价值的指导。
Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host cellular defenses, such as the protein kinase R pathway, which shuts off protein synthesis in response to the dsRNA that accumulates during replication of many viruses. Activation of PKR results in phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), inhibition of protein synthesis, and limited viral replication. VACV encodes two well-characterized antagonists, E3L and K3L, that can block the PKR pathway and thus enable the virus to replicate efficiently. The use of VACV with a deletion of the dominant factor, E3L, enabled the initial identification of PKR antagonists encoded by human cytomegalovirus (HCMV), a prevalent and medically important virus. Understanding the molecular mechanisms of E3L and K3L function facilitated the dissection of the domains, species-specificity, and evolutionary potential of PKR antagonists encoded by human and nonhuman CMVs. While remaining cognizant of the substantial differences in the molecular virology and replication strategies of VACV and CMVs, this review illustrates how VACV can provide a valuable guide for the study of other experimentally less tractable viruses.