Evolutionarily conserved pressure for the existence of distinct G2/M cell cycle arrest and A3H inactivation functions in HIV-1 Vif
Evolutionarily conserved pressure for the existence of distinct G2/M cell cycle arrest and A3H inactivation functions in HIV-1 Vif
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DOI：
10.1080/15384101.2014.1000212
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发表时间：
2015-03-15
期刊：
影响因子：
4.3
通讯作者：
Yu, Xiao-Fang
中科院分区：
文献类型：
--
作者：
Zhao, Ke;Du, Juan;Yu, Xiao-Fang
HIV-1 Vif组装Cul5-EloB/C E3泛素连接酶，诱导细胞抗病毒APOBEC3蛋白的蛋白酶体降解。详细的结构研究已经证实了Vif中的关键功能域，我们之前已经确定这些功能域对EloB/C、Cul5和CBF的相互作用很重要。然而，Vif识别底物的机制仍然知之甚少。已确定Vif的特定区域负责结合和消耗APOBEC3G和APOBEC3F。有趣的是，我们现在已经确定了HIV-1 vif介导的G2/ m期细胞周期阻滞和APOBEC3H降解所需的不同但重叠的结构域，而不是APOBEC3G或APOBEC3F失活所需的结构域。令人惊讶的是，来自原发HIV-1变异的Vif分子导致G2/M阻滞，无法使APOBEC3H失活；另一方面，能够灭活APOBEC3H的HIV-1 Vif变体无法诱导G2/M阻滞。所有这些Vif变异体仍然保持失活APOBEC3G/F的能力。因此，原发HIV-1变异体已经进化成具有不同的功能活动，允许它们使用互排斥的界面结构域抑制APOBEC3H或引起G2细胞周期阻滞。APOBEC3H耗尽和G2阻滞显然是进化选择的特征，不能共存于单个Vif分子上。两种HIV-1 Vif变体的存在和持续存在表明APOBEC3H抑制和细胞周期调节对HIV-1在体内存活的重要性。
HIV-1 Vif assembles the Cul5-EloB/C E3 ubiquitin ligase to induce proteasomal degradation of the cellular antiviral APOBEC3 proteins. Detailed structural studies have confirmed critical functional domains in Vif that we have previously identified as important for the interaction of EloB/C, Cul5, and CBF. However, the mechanism by which Vif recognizes substrates remains poorly understood. Specific regions of Vif have been identified as being responsible for binding and depleting APOBEC3G and APOBEC3F. Interestingly, we have now identified distinct yet overlapping domains that are required for HIV-1 Vif-mediated G2/M-phase cell cycle arrest and APOBEC3H degradation, but not for the inactivation of APOBEC3G or APOBEC3F. Surprisingly, Vif molecules from primary HIV-1 variants that caused G2/M arrest were unable to inactivate APOBEC3H; on the other hand, HIV-1 Vif variants that could inactivate APOBEC3H were unable to induce G2/M arrest. All of these Vif variants still maintained the ability to inactivate APOBEC3G/F. Thus, primary HIV-1 variants have evolved to possess distinct functional activities that allow them to suppress APOBEC3H or cause G2 cell cycle arrest, using mutually exclusive interface domains. APOBEC3H depletion and G2 arrest are apparently evolutionary selected features that cannot co-exist on a single Vif molecule. The existence and persistence of both types of HIV-1 Vif variant suggests the importance of APOBEC3H suppression and cell cycle regulation for HIV-1's survival in vivo.