Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest
Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest
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DOI：
10.1016/j.bbrc.2020.04.123
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发表时间：
2020-06-18
影响因子：
3.1
通讯作者：
Takaori-Kondo, Akifumi
中科院分区：
文献类型：
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作者：
Nagata, Kayoko;Shindo, Keisuke;Takaori-Kondo, Akifumi
HIV-1 Vif 与宿主蛋白形成 E3 泛素连接酶复合物，以抵消宿主限制性 APOBEC3，并且还已知会在 G2 期积累受感染的细胞以促进病毒复制。然而，Vif 如何诱导 G2 停滞的潜在机制尚未完全了解，更具体地说，G2 停滞的直接靶分子尚未确定。在这里，我们发现 B56 家族蛋白 (PP2A-B56)（蛋白磷酸酶 2A 的调节亚基之一）的降解对于 Vif 诱导的 G2 停滞至关重要。 NL4-3 Vif 引起 PP2A-B56 降解，PP2A-B56 的互补克服了 Vif 诱导的停滞。 siRNA 本身敲低 PPP2R5D（PP2A-B56 之一）可诱导未感染细胞的细胞周期停滞。我们还确定了 Vif 残基 I31 和 R 或 K33 是诱导 G2 停滞的决定因素，不引起 G2 停滞的 Vif 变体不会诱导 PPP2R5D 降解，尽管它保持诱导 APOBEC3G 降解的能力，显示 Vif 诱导的停滞与 PP2A-B56 降解之间的强相关性。在 HIV-1 分离株的序列数据库中，大约 43% 的 Vif 菌株含有可能诱导细胞周期停滞的残基，这表明 Vif 诱导的 G2 停滞有助于 HIV-1 体内感染和传播。我们的数据有助于了解 Vif 介导的停滞机制，并深入了解一般细胞周期调控。 (c) 2020 Elsevier Inc. 保留所有权利。
HIV-1 Vif forms an E3 ubiquitin ligase complex with host proteins to counteract host restrictive APOBEC3, and is also known to accumulate infected cells at the G2 phase to promote viral replication. However, the underlying mechanism of how Vif induces G2 arrest is not fully understood, and more specifically, direct target molecules of G2 arrest have not been identified. Here we show that degradation of B56 family proteins (PP2A-B56), one of the regulatory subunits of protein phosphatase 2A, is critical for the Vif-induced G2 arrest. NL4-3 Vif caused degradation of PP2A-B56, and complementation of PP2A-B56 overcome the Vif-induced arrest. Supportively, knockdown of PPP2R5D, one of PP2A-B56, by siRNA itself induced cell cycle arrest of non-infected cells. We also identified Vif residues I31 and R or K33 are determinants for inducing G2 arrest, and Vif variants that did not cause G2 arrest did not induce PPP2R5D degradation, although it maintain the ability to induce APOBEC3G degradation, showing strong correlation between Vif-induced arrest and PP2A-B56 degradation. In a sequence database of HIV-1 isolates, Vif strains harboring residues that presumably induce cell cycle arrest are approximately 43%, suggesting Vif-induced G2 arrest contributes to HIV-1 infection in vivo and spread. Our data help understand the mechanism of Vif-mediated arrest, and gain insights into general cell cycle regulation. (c) 2020 Elsevier Inc. All rights reserved.