State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
Department of Zoology, College of Life Sciences, Nanjing Agriculture University, Nanjing, Jiangsu, People's Republic of China.
Retrovirology. 2020 Jun 29;17(1):16. doi: 10.1186/s12977-020-00524-2.
The human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmic-nuclear transport but was recently reported to restrict HIV-1 replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration. This work explores the mechanisms of MxB-mediated HIV-1 inhibition.
We demonstrated that MxB represses NUP358-mediated PIC nuclear import and HIV-1 replication. Moreover, MxB's effects on PIC nuclear import and HIV-1 replication depend critically on cofactor cleavage and polyadenylation specificity factor subunit 6 (CPSF6). MxB binds nucleoporin NUP358, blocks NUP358-CA interaction, thereby impeding the nuclear import of HIV-1 PIC with CPSF6 binding to PIC. More intriguingly, CPSF6's role in nuclear import depends on MxB, being a facilitator of HIV-1 nuclear import on its own, but becoming an inhibitor when MxB is present.
Our work establishes that MxB impedes the NUP358-mediated HIV-1 nuclear import and viral replication cooperatively with CPSF6.
人类弹状病毒抗性 2（Mx2/MxB）蛋白最初被发现调节细胞质-核运输，但最近有报道称其通过与 HIV-1 衣壳（CA）结合来限制 HIV-1 的复制，从而阻止脱壳、前整合复合物（PIC）的核输入和病毒 DNA 整合。这项工作探讨了 MxB 介导的 HIV-1 抑制的机制。
我们证明了 MxB 抑制 NUP358 介导的 PIC 核输入和 HIV-1 复制。此外，MxB 对 PIC 核输入和 HIV-1 复制的影响严重依赖于辅助因子切割和多聚腺苷酸化特异性因子亚基 6（CPSF6）。MxB 与核孔蛋白 NUP358 结合，阻断 NUP358-CA 相互作用，从而阻止与 CPSF6 结合的 HIV-1 PIC 的核输入。更有趣的是，CPSF6 在核输入中的作用取决于 MxB，它本身可以促进 HIV-1 的核输入，但当 MxB 存在时，它就成为一种抑制剂。
我们的工作确立了 MxB 与 CPSF6 协同阻碍 NUP358 介导的 HIV-1 核输入和病毒复制。
