Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway
Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway
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DOI：
10.1074/jbc.m313093200
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发表时间：
2004-02-27
影响因子：
4.8
通讯作者：
Gabuzda, D
中科院分区：
文献类型：
--
作者：
Mehle, A;Strack, B;Gabuzda, D
病毒必须克服不同的细胞内防御机制才能建立感染。人类免疫缺陷病毒1（HIV-1）的Vif（病毒粒子感染因子）蛋白通过克服APOBEC 3G（CEM 15）的抗病毒活性发挥作用，APOBEC 3G是一种胞苷脱氨酶，可诱导新合成的病毒DNA中的G至A超突变。在不存在Vif的情况下，APOBEC 3G掺入到病毒体中使得HIV-1不具有感染性。我们在这里报告说，Vif抵消APOBEC 3G的抗病毒活性，通过靶向它的泛素-蛋白酶体途径的破坏。Vif与APOBEC 3G形成复合物并增强APOBEC 3G泛素化，导致稳态APOBEC 3G水平降低和蛋白质半衰期缩短。此外，APOBEC 3G的VIF依赖性降解被蛋白酶体抑制剂或泛素突变体K48 R阻断。Vif中高度保守的半胱氨酸突变或保守的SLQ（Y/F）LA基序缺失导致突变体不能诱导APOBEC 3G降解并产生非感染性HIV-1;然而，Vif中破坏病毒复制的保守磷酸化位点突变不影响APOBEC 3G降解，表明Vif除了诱导APOBEC 3G的蛋白酶体降解外，对其他功能也很重要。Vif在没有APOBEC 3G的情况下是单泛素化的，但当APOBEC 3G共表达时，Vif是多泛素化的并迅速降解，这表明共表达加速了两种蛋白质的降解。这些结果表明，Vif通过靶向APOBEC 3G通过泛素-蛋白酶体途径降解发挥作用，并暗示蛋白酶体是微生物和细胞防御之间动态相互作用的位点。
Viruses must overcome diverse intracellular defense mechanisms to establish infection. The Vif (virion infectivity factor) protein of human immunodeficiency virus 1 (HIV-1) acts by overcoming the antiviral activity of APOBEC3G (CEM15), a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. In the absence of Vif, APOBEC3G incorporation into virions renders HIV-1 non-infectious. We report here that Vif counteracts the antiviral activity of APOBEC3G by targeting it for destruction by the ubiquitin-proteasome pathway. Vif forms a complex with APOBEC3G and enhances APOBEC3G ubiquitination, resulting in reduced steady-state APOBEC3G levels and a decrease in protein half-life. Furthermore, Vif-dependent degradation of APOBEC3G is blocked by proteasome inhibitors or ubiquitin mutant K48R. A mutation of highly conserved cysteines or the deletion of a conserved SLQ(Y/F)LA motif in Vif results in mutants that fail to induce APOBEC3G degradation and produce non-infectious HIV-1; however, mutations of conserved phosphorylation sites in Vif that impair viral replication do not affect APOBEC3G degradation, suggesting that Vif is important for other functions in addition to inducing proteasomal degradation of APOBEC3G. Vif is mon-oubiquitinated in the absence of APOBEC3G but is poly-ubiquitinated and rapidly degraded when APOBEC3G is coexpressed, suggesting that coexpression accelerates the degradation of both proteins. These results suggest that Vif functions by targeting APOBEC3G for degradation via the ubiquitin-proteasome pathway and implicate the proteasome as a site of dynamic interplay between microbial and cellular defenses.