Davis David A, Bulut Haydar, Shrestha Prabha, Mitsuya Hiroaki, Yarchoan Robert
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20814, USA.
Antioxidants (Basel). 2022 Oct 18;11(10):2054. doi: 10.3390/antiox11102054.
Most viruses encode their own proteases to carry out viral maturation and these often require dimerization for activity. Studies on human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and human T-cell leukemia virus (HTLV-1) proteases have shown that the activity of these proteases can be reversibly regulated by cysteine (Cys) glutathionylation and/or methionine oxidation (for HIV-2). These modifications lead to inhibition of protease dimerization and therefore loss of activity. These changes are reversible with the cellular enzymes, glutaredoxin or methionine sulfoxide reductase. Perhaps more importantly, as a result, the maturation of retroviral particles can also be regulated through reversible oxidation and this has been demonstrated for HIV-1, HIV-2, Mason-Pfizer monkey virus (M-PMV) and murine leukemia virus (MLV). More recently, our group has learned that SARS-CoV-2 main protease (M) dimerization and activity can also be regulated through reversible glutathionylation of Cys300. Overall, these studies reveal a conserved way for viruses to regulate viral polyprotein processing particularly during oxidative stress and reveal novel targets for the development of inhibitors of dimerization and activity of these important viral enzyme targets.
大多数病毒编码自身的蛋白酶以进行病毒成熟，而这些蛋白酶通常需要二聚化才能发挥活性。对1型人类免疫缺陷病毒（HIV-1）、2型（HIV-2）和人类T细胞白血病病毒（HTLV-1）蛋白酶的研究表明，这些蛋白酶的活性可通过半胱氨酸（Cys）谷胱甘肽化和/或甲硫氨酸氧化（针对HIV-2）进行可逆调节。这些修饰会导致蛋白酶二聚化受到抑制，从而失去活性。这些变化可被细胞内的谷氧还蛋白或甲硫氨酸亚砜还原酶逆转。也许更重要的是，结果显示逆转录病毒颗粒的成熟也可通过可逆氧化来调节，这已在HIV-1、HIV-2、马森- Pfizer猴病毒（M-PMV）和鼠白血病病毒（MLV）中得到证实。最近，我们的研究小组发现严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）主要蛋白酶（M）的二聚化和活性也可通过Cys300的可逆谷胱甘肽化来调节。总体而言，这些研究揭示了病毒调节病毒多聚蛋白加工的一种保守方式，特别是在氧化应激期间，并揭示了开发这些重要病毒酶靶点二聚化和活性抑制剂的新靶点。
