HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase
HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase
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DOI：
10.4161/cc.6.2.3732
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发表时间：
2007-01-15
期刊：
影响因子：
4.3
通讯作者：
Margottin-Goguet, Florence
中科院分区：
文献类型：
--
作者：
Le Rouzic, Erwann;Belaidouni, Nadia;Margottin-Goguet, Florence
HIV1 Vpr 蛋白如何启动宿主细胞反应导致细胞周期停滞在 G(2) 仍不清楚。在这里，我们表明，Vpr 招募 DCAF1/VprBP 对于其细胞抑制活性至关重要，这种活性可以通过损害 DCAF1 结合的 Vpr 单突变或通过 siRNA 介导的 DCAF1 沉默来消除。此外，DCAF1 将 Vpr 桥接到 DDB1，DDB1 是 Cul4 泛素连接酶的核心亚基。总而言之，这些结果表明 Vpr 通过劫持 Cul4/DDB1(DCAF1) 泛素连接酶来触发 G(2) 停滞。我们进一步表明，Vpx（一种由 HIV2 和 SIV 获得的非细胞抑制性 Vpr 相关蛋白）也通过保守基序结合 DCAF1。因此，来自 HIV1 的 Vpr 和来自 SIV 的 Vpx 招募 DCAF1，为宿主细胞带来不同的生理结果。这反过来表明，这两种蛋白质已经进化为保留与相同的 Cul4 泛素连接酶的相互作用，同时在识别蛋白酶体降解的宿主底物方面存在差异。
How the HIV1 Vpr protein initiates the host cell response leading to cell cycle arrest in G(2) has remained unknown. Here, we show that recruitment of DCAF1/VprBP by Vpr is essential for its cytostatic activity, which can be abolished either by single mutations of Vpr that impair DCAF1 binding, or by siRNA-mediated silencing of DCAF1. Furthermore, DCAF1 bridges Vpr to DDB1, a core subunit of Cul4 ubiquitin ligases. Altogether these results point to a mechanism where Vpr triggers G(2) arrest by hijacking the Cul4/DDB1(DCAF1) ubiquitin ligase. We further show that, Vpx, a non-cytostatic Vpr-related protein acquired by HIV2 and SIV, also binds DCAF1 through a conserved motif. Thus, Vpr from HIV1 and Vpx from SIV recruit DCAF1 with different physiological outcomes for the host cell. This in turn suggests that both proteins have evolved to preserve interaction with the same Cul4 ubiquitin ligase while diverging in the recognition of host substrates targeted for proteasomal degradation.