Noncanonical Rab9a action supports retromer-mediated endosomal exit of human papillomavirus during virus entry.
Noncanonical Rab9a action supports retromer-mediated endosomal exit of human papillomavirus during virus entry.
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DOI：
10.1371/journal.ppat.1011648
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发表时间：
2023-09
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影响因子：
6.7
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中科院分区：
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Rab GTP酶在控制细胞内囊泡转运中起关键作用。GTP结合的Rab蛋白支持囊泡运输。在这里，我们报告说，不像细胞蛋白货物，逆转录酶介导的人乳头瘤病毒（HPV）进入逆行转运途径在病毒进入抑制Rab 9a在其GTP结合的形式。Rab 9a的敲低通过调节HPV-逆转录酶相互作用和损害逆转录酶介导的进入病毒的内体至高尔基体转运来抑制HPV进入，导致HPV在内体中积累。Rab 9a在感染后3.5小时就接近HPV，在Rab 7-HPV相互作用之前，并且即使在显性阴性Rab 7存在下，HPV在Rab 9a敲低细胞中也显示出与逆转录聚合物的增加的关联。因此，Rab 9a可以独立于Rab 7调节HPV-逆转录酶结合。令人惊讶的是，过量的GTP-Rab 9a削弱HPV进入，而过量的GDP-Rab 9a减少L2和Rab 9a之间的关联并刺激进入。这些发现揭示了HPV和细胞蛋白在细胞内运输期间以不同的方式利用Rab 9a宿主运输机制。Rab GTP酶是调节细胞内膜结合囊泡转运的小蛋白。典型地，鸟苷三磷酸（GTP）结合的Rab蛋白支持囊泡运输。在这里，我们报告说，与细胞蛋白质货物，GTP结合Rab 9a抑制进入人乳头瘤病毒（HPV）的病毒内囊泡旅行到细胞核。HPV是小型无包膜DNA病毒，可引发约5%的人类癌症。在HPV进入过程中，Rab 9a与病毒颗粒中的L2蛋白结合。Rab 9a的消耗通过调节HPV与逆转录酶（retromer）（一种细胞蛋白运输复合物）的相互作用并在病毒进入期间损害逆转录酶介导的进入病毒的内体至高尔基体运输来抑制HPV感染。这个HPV运输步骤也需要Rab 7，它比Rab 9a晚起作用。令人惊讶的是，过量的GTP结合的Rab 9a损害HPV进入，而过量的鸟苷二磷酸（GDP）结合的Rab 9a刺激进入。HPV L2蛋白最初与GTP-Rab 9a结合，但当Rab 9a转化为GDP结合形式时，L2被转移到Rab 7以进一步运输。我们的研究结果表明，HPV和细胞蛋白在细胞内运输过程中以不同的方式利用Rab 9a宿主运输机制，为治疗方法提供了潜在的脆弱性。
Rab GTPases play key roles in controlling intracellular vesicular transport. GTP-bound Rab proteins support vesicle trafficking. Here, we report that, unlike cellular protein cargos, retromer-mediated delivery of human papillomaviruses (HPV) into the retrograde transport pathway during virus entry is inhibited by Rab9a in its GTP-bound form. Knockdown of Rab9a inhibits HPV entry by modulating the HPV-retromer interaction and impairing retromer-mediated endosome-to-Golgi transport of the incoming virus, resulting in the accumulation of HPV in the endosome. Rab9a is in proximity to HPV as early as 3.5 h post-infection, prior to the Rab7-HPV interaction, and HPV displays increased association with retromer in Rab9a knockdown cells, even in the presence of dominant negative Rab7. Thus, Rab9a can regulate HPV-retromer association independently of Rab7. Surprisingly, excess GTP-Rab9a impairs HPV entry, whereas excess GDP-Rab9a reduces association between L2 and Rab9a and stimulates entry. These findings reveal that HPV and cellular proteins utilize the Rab9a host trafficking machinery in distinct ways during intracellular trafficking. Rab GTPases are small proteins that regulate transport of membrane-bound vesicles inside cells. Canonically, guanosine triphosphate (GTP)-bound Rab proteins support vesicle trafficking. Here, we report that, unlike cellular protein cargos, GTP-bound Rab9a inhibits the entry of human papillomaviruses (HPV) as the virus travels inside vesicles to the nucleus. HPV are small non-enveloped DNA viruses that trigger ~5% of human cancer. During HPV entry, Rab9a associates with the L2 protein in the virus particle. Depletion of Rab9a inhibits HPV infection by modulating the interaction of HPV with retromer, a cellular protein trafficking complex, and impairing retromer-mediated endosome-to-Golgi trafficking of the incoming virus during virus entry. This HPV trafficking step also requires Rab7, which acts later than Rab9a. Surprisingly, excess GTP-bound Rab9a impairs HPV entry, whereas excess guanosine diphosphate (GDP)-bound Rab9a stimulates the entry. The HPV L2 protein initially associates with GTP-Rab9a, but when Rab9a is converted to the GDP-bound form, L2 is transferred to Rab7 for further trafficking. Our findings reveal that HPV and cellular proteins utilize the Rab9a host trafficking machinery in distinct ways during intracellular trafficking, providing a potential vulnerability for therapeutic approaches.
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