Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2024 Mar 5;15(1):2017. doi: 10.1038/s41467-024-46306-8.
HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4 T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4 T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.
HIV-1 感染会增加罹患各种癌症的风险，包括 T 细胞淋巴瘤。HIV-1 编码的蛋白是否直接导致肿瘤发生尚不清楚。我们观察到，HIV-1 感染者血液中的大约 1-5%的 CD4 T 细胞表现出过倍增的中心体，这表明中心体扩增是 HIV-1 相关癌症发生的基础，可导致非整倍体。通过亲和纯化、生化和细胞分析，我们发现 HIV-1 的辅助蛋白 Vpr 劫持了中心体复制机制，诱导中心体扩增和非整倍体。从机制上讲，Vpr 与 E3 连接酶亚基 VprBP 和 Polo 样激酶 4（Plk4）形成协同的三元复合物。然而出乎意料的是，该复合物通过促进其向起始中心体组装的重新定位来增强 Plk4 的功能，并诱导中心体扩增。缺失 Vpr 的 C 端 17 个残基或 VprBP 的酸性区域（与 Plk4 隐蔽的 Polo 框结合所必需的两个元件），都会使 Vpr 丧失诱导这些事件的能力。此外，HIV-1 WT，但不是其 Vpr 突变体，可诱导人原代 CD4 T 细胞中出现多个中心体和非整倍体。我们提出，Vpr•VprBP•Plk4 复合物是连接 HIV-1 感染与肿瘤发生的分子纽带，抑制 Vpr C 端基序可能会降低 HIV-1 相关癌症的发生。
