Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation
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DOI：
10.1038/s41467-019-08810-0
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发表时间：
2019-02-25
影响因子：
16.6
通讯作者：
Giacca, Mauro
中科院分区：
文献类型：
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作者：
Ali, Hashim;Mano, Miguel;Giacca, Mauro
生产性HIV-1复制需要病毒整合酶（IN），它催化病毒基因组整合到宿主细胞DNA中。然而，IN是短暂的，并迅速降解的主机泛素-蛋白酶体系统。为了鉴定负责HIV-1 IN降解的细胞因子，我们使用高含量显微镜使用针对泛素缀合机制的所有组分的siRNA文库进行靶向RNAi筛选。在这里，我们报告说，E3环连接酶TRIM 33是HIV-1 IN稳定性的主要决定因素。TRIM 33敲低的CD 4阳性细胞显示HIV-1复制和前病毒DNA形成增加，而那些过表达该因子的细胞显示相反的效果。TRIM 33的敲低使携带IN丝氨酸57取代为丙氨酸的HIV-1分子克隆的表型恢复，该突变已知会损害病毒DNA整合。因此，TRIM 33通过阻止前病毒形成而作为限制HIV-1感染的细胞因子。
Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we performed a targeted RNAi screen using a library of siRNAs against all components of the ubiquitin-conjugation machinery using high-content microscopy. Here we report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNA formation, while those overexpressing the factor display opposite effects. Knock down of TRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of IN serine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation.