Rab GTPases 控制细胞内囊泡运输，包括人乳头瘤病毒 (HPV) 在进入细胞期间的逆行运输，引导病毒从内体进入跨高尔基体网络 (TGN)、高尔基体，并最终进入细胞核。 Rab 蛋白已被鉴定出在 HPV 到达 TGN 之前起作用，但在进入后期阶段起作用的 Rab 蛋白仍然难以捉摸。在这里，我们报道了 Rab6a 的敲低通过阻止 HPV 从 TGN 退出并阻碍传入病毒在高尔基体内的运输来损害 HPV 进入。 Rab6a 通过促进 HPV 与 TGN 中动力蛋白（一种运动蛋白复合物）和 BICD2（一种动力蛋白接头）的结合来支持 HPV 贩运。 L2 在体外可以直接与 GTP-Rab6a 结合，过量的 GTP-Rab6a 或 GDP-Rab6 会抑制 HPV 进入，这表明 GDP-Rab6 和 GTP-Rab6 之间的循环至关重要。值得注意的是，Rab6a 对于感染细胞 TGN 中的 HPV-BICD2 和 HPV-动力蛋白关联至关重要，但在内体中则不然。我们的研究结果揭示了 HPV 感染分子基础的重要特征，包括发现 HPV 在进入过程中的不同时间使用不同的机制与动力蛋白结合，并确定了抑制 HPV 感染的治疗方法的潜在靶标。人乳头瘤病毒 (HPV) 很小，无包膜 DNA 病毒导致约 5% 的人类癌症。与大多数其他 DNA 病毒一样，HPV 在病毒进入细胞核时会转运至细胞核，从而成功感染细胞。我们在这里展示了 HPV 在病毒进入过程中利用细胞酶 Rab6a 来接合动力蛋白分子马达以沿着微管运输。 Rab6a 是 HPV L2 衣壳蛋白、动力蛋白和跨高尔基体网络 (TGN) 中的动力蛋白接头 BICD2 之间形成复合物所必需的。当传入的病毒进入细胞核时，需要该复合物将其从 TGN 中运输出来。我们的研究结果确定了治疗方法的潜在目标。

Rab GTPases control intracellular vesicular transport, including retrograde trafficking of human papillomavirus (HPV) during cell entry, guiding the virus from the endosome to the trans-Golgi network (TGN), the Golgi apparatus, and eventually the nucleus. Rab proteins have been identified that act prior to the arrival of HPV at the TGN, but Rab proteins operating in later stages of entry remain elusive. Here, we report that knockdown of Rab6a impairs HPV entry by preventing HPV exit from the TGN and impeding intra-Golgi transport of the incoming virus. Rab6a supports HPV trafficking by facilitating the association of HPV with dynein, a motor protein complex, and BICD2, a dynein adaptor, in the TGN. L2 can bind directly to GTP-Rab6a in vitro, and excess of either GTP-Rab6a or GDP-Rab6 inhibits HPV entry, suggesting that cycling between GDP-Rab6 and GTP-Rab6 is critical. Notably, Rab6a is crucial for HPV-BICD2 and HPV-dynein association in the TGN of infected cells but not in the endosome. Our findings reveal important features of the molecular basis of HPV infection, including the discovery that HPV uses different mechanisms to engage dynein at different times during entry, and identify potential targets for therapeutic approaches to inhibit HPV infection.Human papillomaviruses (HPVs) are small, non-enveloped DNA viruses that cause approximately 5% of human cancer. Like most other DNA viruses, HPV traffics to the nucleus during virus entry to successfully infect cells. We show here that HPV utilizes a cellular enzyme, Rab6a, during virus entry to engage the dynein molecular motor for transport along microtubules. Rab6a is required for complex formation between the HPV L2 capsid protein, dynein, and the dynein adaptor BICD2 in the trans-Golgi network (TGN). This complex is required for transport of the incoming virus out of the TGN as it journeys to the nucleus. Our findings identify potential targets for therapeutic approaches.