Antiretroviral activity of TRIM5alpha

描述(申请人提供)：一些哺乳动物，包括灵长类动物，在病毒复制的早期阶段表达显性限制因子，阻止某些逆转录病毒的感染。TRIM51在某些物种中是一种名为TRIMCyp的TRIM5-亲环素A融合蛋白，当逆转录病毒衣壳进入宿主细胞细胞质时，它通过结合逆转录病毒衣壳来调节这些早期阻断。TRIM51是三方基序(TRIM)家族的成员，含有环、B-盒2、卷曲螺旋和B30.2/spry结构域。卷曲的线圈有助于TRIM51的二聚化；B30.2/spry结构域有助于衣壳的识别。环和B-box 2结构域在TRIM51介导的逆转录病毒限制性内切酶中的功能还不是很清楚。这些结构域有助于逆转录病毒限制的效力，这被认为涉及加速揭开病毒衣壳。这一竞争性更新应用的总体目标是了解TRIM51介导的逆转录病毒限制的分子机制，并确定单个TRIM51结构域和衣壳元件在病毒识别和抑制中的作用。这项建议的具体目的是：1)探讨TRIM51 B-box 2结构域在逆转录病毒限制中的作用；2)了解TRIM51环域的E3泛素连接酶活性对逆转录病毒限制的作用；3)测试TRIM51介导的逆转录病毒限制的机制模型；以及4)确定逆转录病毒衣壳的变化如何影响与TRIM51和宿主细胞辅助因子(如亲环素A)的相互作用。公共卫生相关性：包括人类在内的许多哺乳动物的细胞表达能够阻断包括人类免疫缺陷病毒(HIV-1)在内的逆转录病毒感染的TRIM51蛋白。拟议的工作将试图了解TRIM51是如何工作的，以及如何改进其活动。

DESCRIPTION (provided by applicant): Some mammals, including primates, express dominant restriction factors that block the infection of certain retroviruses during the early phase of virus replication. TRIM51 or, in some species, a TRIM5- cyclophilin A fusion protein called TRIMCyp, mediates these early blocks by binding the retroviral capsid as it enters the host cell cytoplasm. TRIM51 is a member of the tripartite motif (TRIM) family of proteins and contains RING, B-box 2, coiled coil and B30.2/SPRY domains. The coiled coil contributes to TRIM51 dimerization; the B30.2/SPRY domain contributes to capsid recognition. The functions of the RING and B-box 2 domains in TRIM51-mediated retroviral restriction are less well understood. These domains contribute to the potency of retrovirus restriction, which is thought to involve the accelerated uncoating the viral capsid. The overall goal of this competing renewal application is to understand the molecular mechanism of TRIM51- mediated retrovirus restriction and to define the roles of individual TRIM51 domains and capsid elements in virus recognition and inhibition. The specific aims of this proposal are: 1) To investigate the role of the TRIM51 B-box 2 domain in retrovirus restriction; 2) To investigate the contribution of the E3 ubiquitin ligase activity of the TRIM51 RING domain to retrovirus restriction; 3) To test mechanistic models of TRIM51-mediated retrovirus restriction; and 4) To define how changes in the retroviral capsid influence interaction with TRIM51 and host cell cofactors such as cyclophilin A. PUBLIC HEALTH RELEVANCE: The cells of many mammals, including humans, express TRIM51 proteins that can block infection by retroviruses, including human immunodeficiency virus (HIV-1). The proposed work will attempt to understand how TRIM51 works and how its activity can be improved.