Distinct functions of diaphanous-related formins regulate HIV-1 uncoating and transport
Distinct functions of diaphanous-related formins regulate HIV-1 uncoating and transport
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DOI：
10.1073/pnas.1700247114
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发表时间：
2017-08-15
影响因子：
11.1
通讯作者：
Naghavi, Mojgan H.
中科院分区：
文献类型：
--
作者：
Delaney, Michael Keegan;Malikov, Viacheslav;Naghavi, Mojgan H.
透明 (Dia) 相关福明 (DRF) 通过控制肌动蛋白成核和微管 (MT) 稳定来协调细胞骨架重塑，以促进细胞极化和迁移等过程；但他们活动的全部范围仍不得而知。在这里，我们揭示了 DRF 在早期人类免疫缺陷病毒 1 型 (HIV-1) 感染过程中的两个不同的作用和功能。独立于肌动蛋白调节活性，Dia1 和 Dia2 促进 HIV-1 诱导的 MT 稳定和病毒颗粒的细胞内运动。然而，DRF 还结合体外组装的衣壳核衣壳复合物并促进 HIV-1 衣壳 (CA) 壳的解体。这个过程也称为“脱壳”，是病毒生命周期中人们最了解的阶段之一。结构域分析和结构建模表明，Dia2 结合病毒 CA 并介导脱壳和早期感染的区域包含卷曲螺旋结构域，并且这些活性在遗传上与 MT 稳定的影响是分开的。我们的研究结果表明，HIV-1 利用 DRF 的离散功能来协调早期感染的关键步骤，并确定 Dia 家族成员是人们知之甚少的 HIV-1 脱壳过程的调节者。
Diaphanous (Dia)-related formins (DRFs) coordinate cytoskeletal remodeling by controlling actin nucleation and microtubule (MT) stabilization to facilitate processes such as cell polarization and migration; yet the full extent of their activities remains unknown. Here, we uncover two discrete roles and functions of DRFs during early human immunodeficiency virus type 1 (HIV-1) infection. Independent of their actin regulatory activities, Dia1 and Dia2 facilitated HIV-1-induced MT stabilization and the intracellular motility of virus particles. However, DRFs also bound in vitro assembled capsidnucleocapsid complexes and promoted the disassembly of HIV-1 capsid (CA) shell. This process, also known as "uncoating," is among the most poorly understood stages in the viral lifecycle. Domain analysis and structure modeling revealed that regions of Dia2 that bound viral CA and mediated uncoating as well as early infection contained coiled-coil domains, and that these activities were genetically separable from effects on MT stabilization. Our findings reveal that HIV-1 exploits discrete functions of DRFs to coordinate critical steps in early infection and identifies Dia family members as regulators of the poorly understood process of HIV-1 uncoating.