Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA
J Biol Chem. 2020 Aug 14;295(33):11513-11528. doi: 10.1074/jbc.REV120.012784. Epub 2020 Jun 16.
Viperin plays an important and multifaceted role in the innate immune response to viral infection. Viperin is also notable as one of very few radical SAM-dependent enzymes present in higher animals; however, the enzyme appears broadly conserved across all kingdoms of life, which suggests that it represents an ancient defense mechanism against viral infections. Although viperin was discovered some 20 years ago, only recently was the enzyme's structure determined and its catalytic activity elucidated. The enzyme converts CTP to 3'-deoxy-3',4'-didehydro-CTP, which functions as novel chain-terminating antiviral nucleotide when misincorporated by viral RNA-dependent RNA polymerases. Moreover, in higher animals, viperin interacts with numerous other host and viral proteins, and it is apparent that this complex network of interactions constitutes another important aspect of the protein's antiviral activity. An emerging theme is that viperin appears to facilitate ubiquitin-dependent proteasomal degradation of some of the proteins it interacts with. Viperin-targeted protein degradation contributes to the antiviral response either by down-regulating various metabolic pathways important for viral replication or by directly targeting viral proteins for degradation. Here, we review recent advances in our understanding of the structure and catalytic activity of viperin, together with studies investigating the interactions between viperin and its target proteins. These studies have provided detailed insights into the biochemical processes underpinning this unusual enzyme's wide-ranging antiviral activity. We also highlight recent intriguing reports that implicate a broader role for viperin in regulating nonpathological cellular processes, including thermogenesis and protein secretion.
抗病毒蛋白（Viperin）在先天免疫应对病毒感染中发挥着重要而多方面的作用。作为高等动物中极少数存在的依赖于自由基 S-腺苷甲硫氨酸（SAM）的酶之一，抗病毒蛋白也值得注意；然而，该酶在所有生命领域中都广泛保守，这表明它代表了一种古老的抗病毒感染防御机制。尽管抗病毒蛋白在 20 年前就被发现，但直到最近才确定了该酶的结构并阐明了其催化活性。该酶将 CTP 转化为 3'-脱氧-3'、4'-二脱氢-CTP，当被病毒 RNA 依赖性 RNA 聚合酶错误掺入时，该物质充当新型链终止抗病毒核苷酸。此外，在高等动物中，抗病毒蛋白与许多其他宿主和病毒蛋白相互作用，显然，这种复杂的相互作用网络构成了该蛋白抗病毒活性的另一个重要方面。一个新兴主题是，抗病毒蛋白似乎促进了与其相互作用的一些蛋白的泛素依赖性蛋白酶体降解。抗病毒蛋白靶向的蛋白降解通过下调对病毒复制重要的各种代谢途径，或者通过直接靶向病毒蛋白进行降解，从而有助于抗病毒反应。在这里，我们综述了最近在抗病毒蛋白的结构和催化活性方面的理解进展，以及研究抗病毒蛋白与其靶蛋白之间相互作用的研究进展。这些研究为该不寻常酶的广泛抗病毒活性的生化过程提供了详细的见解。我们还强调了最近引人关注的报告，这些报告表明抗病毒蛋白在调节非病理性细胞过程（包括产热和蛋白质分泌）方面发挥着更广泛的作用。
