CPSF6 defines a conserved capsid interface that modulates HIV-1 replication.
CPSF6 defines a conserved capsid interface that modulates HIV-1 replication.
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DOI：
10.1371/journal.ppat.1002896
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
James LC
中科院分区：
文献类型：
--
作者：
Price AJ;Fletcher AJ;Schaller T;Elliott T;Lee K;KewalRamani VN;Chin JW;Towers GJ;James LC
HIV-1基因组进入由衣壳（CA）蛋白组成的外壳内的细胞。CA序列的变异改变了HIV-1的感染性和逃避宿主限制因子的能力。然而，除了亲环素A结合环，CA没有已知的界面与细胞辅因子相互作用。在这里，我们描述了一种新的蛋白质-蛋白质界面的N-末端结构域的HIV-1 CA，确定由X-射线晶体学，介导病毒的限制和宿主辅因子的依赖性。该界面在慢病毒中高度保守，并且在六聚体晶格的背景下是可访问的。界面的突变阻止了与CPSF 6 -358的结合和限制，CPSF 6 -358是RNA加工因子、切割和多聚腺苷酸化特异性因子6（CPSF 6）的截短胞质形式。此外，阻止CPSF 6结合的突变也减轻了对核进入辅因子TNPO 3和RanBP 2的依赖。这些结果表明，HIV-1衣壳介导直接的宿主辅因子相互作用，以促进病毒感染。为了感染宿主细胞，HIV-1必须与细胞辅因子相互作用并利用细胞辅因子。衣壳（病毒周围的蛋白质外壳）内的突变已被证明会影响病毒对这些辅因子的使用和对宿主抗病毒蛋白的易感性。然而，除了亲环素A结合环之外，衣壳上没有介导与细胞蛋白相互作用的确定的蛋白质界面。在这里，我们描述了一个保守的界面上的HIV-1衣壳结合宿主蛋白CPSF 6和确定病毒依赖于核转运辅因子的鉴定。这些数据说明了宿主-病毒相互作用如何使HIV-1搭便车进入细胞核，并揭示了抗病毒药物的潜在新靶点。
The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a novel protein-protein interface in the N-terminal domain of HIV-1 CA, determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence. The interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Mutation of the interface prevents binding to and restriction by CPSF6-358, a truncated cytosolic form of the RNA processing factor, cleavage and polyadenylation specific factor 6 (CPSF6). Furthermore, mutations that prevent CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. These results suggest that the HIV-1 capsid mediates direct host cofactor interactions to facilitate viral infection. In order to infect a host cell, HIV-1 must interact with and exploit cellular cofactors. Mutations within capsid, the protein shell that surrounds the virus, have been shown to affect virus usage of these cofactors and susceptibility to host antiviral proteins. However, with the exception of the Cyclophilin A-binding loop, there is no defined protein interface on the capsid that mediates interactions with cellular proteins. Here, we describe the identification of a conserved interface on HIV-1 capsid that binds the host protein CPSF6 and determines viral dependence on nuclear transport cofactors. This data illustrates how host-virus interactions allow HIV-1 to hitch a ride into the nucleus and reveals a potential new target for antiviral drugs.
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影响因子：
6.7
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
通讯作者：
Butler SL
影响因子：
3.3
作者：
De Iaco A;Luban J
通讯作者：
Luban J
影响因子：
3.3
作者：
Cribier A;Ségéral E;Delelis O;Parissi V;Simon A;Ruff M;Benarous R;Emiliani S
通讯作者：
Emiliani S
影响因子：
30.3
作者：
Lee K;Ambrose Z;Martin TD;Oztop I;Mulky A;Julias JG;Vandegraaff N;Baumann JG;Wang R;Yuen W;Takemura T;Shelton K;Taniuchi I;Li Y;Sodroski J;Littman DR;Coffin JM;Hughes SH;Unutmaz D;Engelman A;KewalRamani VN
通讯作者：
KewalRamani VN
影响因子：
5.4
作者：
Fassati, A;Goff, SP
通讯作者：
Goff, SP