State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Virol Sin. 2021 Feb;36(1):85-94. doi: 10.1007/s12250-020-00249-8. Epub 2020 Jul 6.
The human myxovirus resistance 2 (Mx2/MxB) protein, a member of interferon (IFN)-inducible dynamin-like large GTPases, restricts a number of virus infections. Inhibition of these viruses occurs at poorly-defined steps after viral entry and has a common requirement for MxB oligomerization. However, the GTPase activity is essential for the anti-viral effects of MxB against herpesviruses and HBV but not HIV-1. To understand the role of MxB GTPase activity, including GTP binding and GTP hydrolysis, in restriction of HIV-1 infection, we genetically separated these two functions and evaluated their contributions to restriction. We found that both the GTP binding and hydrolysis function of MxB involved in the restriction of HIV-1 replication. The GTPase activity of MxB contributed to its nuclear location, interaction with nucleoporins (NUPs) and HIV-1 capsids. Furthermore, MxB disrupted the association between NUPs and HIV-1 cores dependently upon its GTPase activity. The function of GTPase activity was therefore multi-faceted, led to fundamentally distinct mechanisms employed by wild-type MxB and GTPase activity defective MxB mutations to restrict HIV-1 replication.
人类粘病毒抗性 2（Mx2/MxB）蛋白是干扰素（IFN）诱导的动蛋白样大 GTP 酶家族的成员，它可以限制多种病毒的感染。在病毒进入后，这些病毒的抑制作用发生在定义不明确的步骤，并且普遍需要 MxB 寡聚化。然而，GTP 酶活性对于 MxB 抗疱疹病毒和乙型肝炎病毒的抗病毒作用是必需的，但对 HIV-1 则不是。为了了解 MxB GTP 酶活性（包括 GTP 结合和 GTP 水解）在限制 HIV-1 感染中的作用，我们对这些功能进行了遗传分离，并评估了它们对限制的贡献。我们发现，MxB 的 GTP 结合和水解功能都参与了 HIV-1 复制的限制。MxB 的 GTP 酶活性有助于其核定位、与核孔蛋白（NUPs）和 HIV-1 衣壳的相互作用。此外，MxB 的 GTP 酶活性还依赖于其 GTP 酶活性，破坏了 NUPs 与 HIV-1 核心之间的联系。因此，GTP 酶活性的功能是多方面的，导致野生型 MxB 和 GTP 酶活性缺陷型 MxB 突变体限制 HIV-1 复制所采用的机制根本不同。
