Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
J Virol. 2013 Jul;87(13):7234-45. doi: 10.1128/JVI.00620-13. Epub 2013 May 1.
The tripartite motif protein TRIM5α restricts particular retrovirus infections by binding to the incoming capsid and inhibiting the early stage of virus infection. The TRIM5α RING domain exhibits E3 ubiquitin ligase activity and assists the higher-order association of TRIM5α dimers, which promotes capsid binding. We characterized a panel of RING domain mutants of the rhesus monkey TRIM5α (TRIM5α(rh)) protein. The RING domain function that significantly contributed to retroviral restriction depended upon the restricted virus. The E3 ubiquitin ligase activity of the RING domain contributes to the potency of HIV-1 restriction. Nonetheless, TRIM5α(rh) mutants without detectable E3 ubiquitin ligase activity still blocked reverse transcription and inhibited HIV-1 infection at a moderate level. When TRIM5α(rh) capsid binding was weakened by substitution with a less efficient B30.2/SPRY domain, the promotion of higher-order association by the RING domain was more important to HIV-1 restriction than its E3 ubiquitin ligase activity. For the restriction of N-tropic murine leukemia virus (N-MLV) and equine infectious anemia virus (EIAV) infection, promotion of higher-order association represented the major contribution of the RING domain. Thus, both identity of the target virus and the B30.2/SPRY domain-mediated affinity for the viral capsid determine the relative contribution of the two known RING domain functions to TRIM5α restriction of retrovirus infection.
三结构域蛋白 TRIM5α 通过与进入的衣壳结合并抑制病毒感染的早期阶段来限制特定的逆转录病毒感染。TRIM5α 的 RING 结构域具有 E3 泛素连接酶活性，并协助 TRIM5α 二聚体的高阶缔合，从而促进衣壳结合。我们对恒河猴 TRIM5α（TRIM5α(rh)）蛋白的 RING 结构域进行了一组突变体的表征。对受限制病毒具有显著贡献的 RING 结构域功能。RING 结构域的 E3 泛素连接酶活性有助于 HIV-1 的限制。尽管如此，缺乏可检测的 E3 泛素连接酶活性的 TRIM5α(rh)突变体仍然可以阻断逆转录并以中等水平抑制 HIV-1 感染。当 TRIM5α(rh)衣壳结合因用效率较低的 B30.2/SPRY 结构域取代而减弱时，RING 结构域对高阶缔合的促进作用对 HIV-1 限制比其 E3 泛素连接酶活性更为重要。对于 N 嗜性鼠白血病病毒（N-MLV）和马传染性贫血病毒（EIAV）感染的限制，高阶缔合的促进作用是 RING 结构域的主要贡献。因此，靶病毒的身份和 B30.2/SPRY 结构域介导的对病毒衣壳的亲和力决定了两个已知的 RING 结构域功能对 TRIM5α 限制逆转录病毒感染的相对贡献。
