Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2.
Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2.
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DOI：
10.7554/elife.35738
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发表时间：
2018-08-07
期刊：
影响因子：
7.7
通讯作者：
Bieniasz PD
中科院分区：
文献类型：
--
作者：
Kane M;Rebensburg SV;Takata MA;Zang TM;Yamashita M;Kvaratskhelia M;Bieniasz PD
HIV-1通过一个不明确的过程访问间期细胞的核DNA，该过程涉及衣壳蛋白(CA)和核孔蛋白(NUP)之间的功能相互作用。在这里，我们表明HIV-1CA可以结合多个NUP，并且Nup水平的自然和人为变化都以一种显著依赖于细胞类型、细胞周期和亲环素A(CypA)的方式影响HIV-1感染。我们还发现NUPS介导了抗病毒蛋白MX2的功能，并且MX2可以不同程度地抑制非病毒的NLS功能。值得注意的是，亲环素A和MX2对各种HIV-1 CA突变体的增强和抑制作用都可以通过操纵Nup93亚复合体、Nup62亚复合体、NUP88、NUP214、RANBP2或NUP153的水平来诱导或取消。我们的发现表明，HIV-1以细胞类型、细胞周期、CypA和CA序列依赖的方式不同地利用几条依赖于Nup的“途径”来靶向宿主DNA，并被MX2差异地抑制。
HIV-1 accesses the nuclear DNA of interphase cells via a poorly defined process involving functional interactions between the capsid protein (CA) and nucleoporins (Nups). Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP214, RANBP2, or NUP153. Our findings suggest that several Nup-dependent ‘pathways’ are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.