Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
Elife. 2019 Aug 9;8:e48318. doi: 10.7554/eLife.48318.
The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.
宿主因子载脂蛋白 B mRNA 编辑酶催化多肽样 3G（APOBEC3G，A3G）的抗病毒活性及其介导的人类免疫缺陷病毒 1 型（HIV-1）Vif 蛋白降解是重要的课题。尽管越来越多的证据表明去泛素化酶（DUBs）在先天免疫中很重要，但尚不清楚它们是否参与 A3G 的稳定性。在这里，我们发现 USP49 与 A3G 直接相互作用，并有效地去除泛素，从而增加 A3G 蛋白的表达，并显著增强其抗 HIV-1 活性。出乎意料的是，A3G 的降解也由一种 Vif 和环指独立的途径介导，USP49 可有效拮抗该途径。此外，临床数据表明，USP49 与 A3G 蛋白表达和 Vif 阳性前病毒中的高突变相关，与 HIV-1 潜伏库中完整前病毒的比例呈负相关。我们的研究表明了一种有效稳定 A3G 表达的机制，这可能成为控制 HIV-1 感染和清除潜伏库的靶点。
