Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.
Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.
复制标题
DOI：
10.1016/j.virusres.2016.07.009
复制
发表时间：
2016-09-02
期刊：
影响因子：
5
通讯作者：
Park IW
中科院分区：
文献类型：
--
作者：
Pyeon D;Timani KA;Gulraiz F;He JJ;Park IW
HIV-1 Nef是HIV-1相关的AIDS致病性所必需的，并且可能是足够的，因为单独敲除Nef可以保护HIV感染患者免受AIDS。因此，我们研究了物理敲除Nef的可行性，在HIV-1感染的细胞中使用宿主泛素蛋白酶体系统。我们的免疫共沉淀分析表明Nef与泛素特异性蛋白酶15（USP 15）相互作用，并且已知稳定细胞蛋白的USP 15降解Nef。Nef也可引起USP 15的降解，尽管Nef介导的USP 15降解弱于USP 15介导的Nef降解。Nef和USP 15之间的直接相互作用对于观察到的蛋白质的相互衰变是必不可少的。此外，USP 15不仅降解Nef，而且降解HIV-1结构蛋白Gag，从而基本上抑制HIV-1复制。然而，Gag不降解USP 15，这表明Nef和USP 15复合物与其他病毒蛋白不同，在协调病毒蛋白降解和HIV-1复制中起着不可或缺的作用。此外，Nef和USP 15全面抑制细胞蛋白的泛素化，表明这些蛋白是细胞和病毒蛋白稳定性的主要决定因素。综上所述，这些数据表明Nef和USP 15在调节病毒和细胞蛋白的降解以及因此HIV-1复制中至关重要，并且USP 15对病毒而非细胞蛋白的特异性降解表明USP 15是通过USP 15介导的蛋白体降解从感染细胞中消除病毒蛋白来对抗AIDS的候选治疗剂。
HIV-1 Nef is necessary and may be sufficient for HIV-1-associated AIDS pathogenicity, in that knockout of Nef alone can protect HIV-infected patients from AIDS. We therefore investigated the feasibility of physical knockout of Nef, using the host ubiquitin proteasome system in HIV-1-infected cells. Our co-immunoprecipitation analysis demonstrated that Nef interacted with ubiquitin specific protease 15 (USP15), and that USP15, which is known to stabilize cellular proteins, degraded Nef. Nef could also cause decay of USP15, although Nef-mediated degradation of USP15 was weaker than USP15-mediated Nef degradation. Direct interaction between Nef and USP15 was essential for the observed reciprocal decay of the proteins. Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication. However, Gag did not degrade USP15, indicating that the Nef and USP15 complex, in distinction to other viral proteins, play an integral role in coordinating viral protein degradation and hence HIV-1 replication. Moreover, Nef and USP15 globally suppressed ubiquitylation of cellular proteins, indicating that these proteins are major determinants for the stability of cellular as well as viral proteins. Taken together, these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins, by USP15 points to USP15 as a candidate therapeutic agent to combat AIDS by eliminating viral proteins from the infected cells via USP15-mediated proteosomal degradation.
登录
查看更多内容
影响因子：
3.3
作者：
Dubé M;Bego MG;Paquay C;Cohen ÉA
通讯作者：
Cohen ÉA
影响因子：
6.7
作者：
Kutluay SB;Perez-Caballero D;Bieniasz PD
通讯作者：
Bieniasz PD
影响因子：
64.5
作者：
KESTLER, HW;RINGLER, DJ;DESROSIERS, RC
通讯作者：
DESROSIERS, RC
影响因子：
64.5
作者：
Hanna, Z;Kay, DG;Jolicoeur, P
通讯作者：
Jolicoeur, P
影响因子：
56.9
作者：
KALPANA, GV;MARMON, S;GOFF, SP
通讯作者：
GOFF, SP