Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation
Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation
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DOI：
10.1101/gad.1249904
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发表时间：
2004-12-01
影响因子：
10.5
通讯作者：
Gabuzda, D
中科院分区：
文献类型：
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作者：
Mehle, A;Goncalves, J;Gabuzda, D
HIV-1 Vif（病毒感染因子）蛋白通过靶向蛋白酶体降解来克服 DNA 脱氨酶 APOBEC3G 的抗病毒活性。我们在这里报告，Vif 通过结合 EloC 的新型 SOCS（细胞因子信号传导抑制子）盒形成包含 Cullin 5 和 Elongins B 和 C (Cul5-EloB-EloC) 的 SCF 样 E3 泛素连接酶，从而靶向 APOBEC3G 进行降解。 Vif 与 EloC 的结合受到 SOCS-box BC-box 基序中丝氨酸磷酸化的负调节。 Vif 泛素化在体外和体内均由 Cul5 促进，并且需要完整的 SOCS 盒。因此，Vif 的自动泛素化发生在组装的 Vif-Cul5 复合物内，类似于在其 SCF (Skp1-Cullin-F-box) 复合物内自动泛素化的 F-box 蛋白。这些发现表明，通过 SOCS-box 蛋白的磷酸化或自泛素化来调节 Cul5 E3 复合物的组装和活性，并确定 Vif 和可能作为治疗靶点的宿主细胞蛋白之间的相互作用。
HIV-1 Vif (viral infectivity factor) protein overcomes the antiviral activity of the DNA deaminase APOBEC3G by targeting it for proteasomal degradation. We report here that Vif targets APOBEC3G for degradation by forming an SCF-like E3 ubiquitin ligase containing Cullin 5 and Elongins B and C (Cul5-EloB-EloC) through a novel SOCS (suppressor of cytokine signaling)-box that binds EloC. Vif binding to EloC is negatively regulated by serine phosphorylation in the BC-box motif of the SOCS-box. Vif ubiquitination is promoted by Cul5 in vitro and in vivo, and requires an intact SOCS-box. Thus, auto-ubiquitination of Vif occurs within the assembled Vif-Cul5 complex, analogous to F-box proteins that are autoubiquitinated within their SCF (Skp1-Cullin-F-box) complex. These findings suggest mechanisms that regulate the assembly and activity of Cul5 E3 complexes through phosphorylation or autoubiquitination of the SOCS-box protein, and identify interactions between Vif and host cell proteins that may be therapeutic targets.