Wei Min, Zhao Xia, Liu Mi, Huang Zhi, Xiao Yong, Niu Meijuan, Shao Yiming, Kleiman Lawrence
School of Medicine, Nankai University, Tianjin, China, 300071.
Lady Davis Institute, Jewish General Hospital, McGill University, Canada, H3T 1E2.
Sci Rep. 2015 Oct 1;5:14724. doi: 10.1038/srep14724.
Human Immunodeficiency Virus type 1 (HIV-1) major structure protein Gag is synthesized in the cytoplasm, assembles on the plasma membrane, subsequently buds and releases. HIV-1 viral particles incorporate a number of host proteins to facilitate or inhibit HIV-1 replication. Here we identify a new host protein, coiled-coil domain containing protein 8 (CCDC8), in HIV-1 particles. Incorporation of CCDC8 into virions is dependent on the interaction between CCDC8 and Gag matrix region. Exogenous overexpression of CCDC8 can strongly inhibit HIV-1 production, up to ~30 fold. CCDC8 is a membrane-associated protein. The interaction between exogenously expressed CCDC8 and Gag on the plasma membrane changes the assembly of Gag, and redirects it into intracellular sites, or causes Gag endocytosis. CCDC8, along with cytoskeleton protein obscuring-like1 (Obsl1) and E3 ligase Cul7, induces Gag polyubiquitination and degradation. Thus we identify a new host protein and a new pathway for HIV-1 Gag polyubiquitination and degradation. This pathway presents potential therapeutic strategies against HIV infection.
1型人类免疫缺陷病毒（HIV-1）的主要结构蛋白Gag在细胞质中合成，在质膜上组装，随后出芽并释放。HIV-1病毒颗粒包含多种宿主蛋白，以促进或抑制HIV-1复制。在此，我们在HIV-1颗粒中鉴定出一种新的宿主蛋白，即含卷曲螺旋结构域蛋白8（CCDC8）。CCDC8整合到病毒粒子中依赖于CCDC8与Gag基质区域之间的相互作用。外源性过表达CCDC8可强烈抑制HIV-1产生，抑制幅度高达约30倍。CCDC8是一种膜相关蛋白。外源性表达的CCDC8与质膜上的Gag之间的相互作用改变了Gag的组装，并将其重新导向细胞内位点，或导致Gag内吞。CCDC8与细胞骨架蛋白类 obscuring样蛋白1（Obsl1）和E3连接酶Cul7一起，诱导Gag多聚泛素化和降解。因此，我们鉴定出一种新的宿主蛋白以及HIV-1 Gag多聚泛素化和降解的新途径。该途径为抗HIV感染提供了潜在的治疗策略。
