Park Jung-Eun, Kim Tae-Sung, Zeng Yan, Monnie Christina M, Alam Muhammad S, Zhou Ming, Mikolaj Melissa, Maldarelli Frank, Narayan Kedar, Ahn Jinwoo, Ashwell Jonathan D, Strebel Klaus, Lee Kyung S
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
These authors contributed equally to this work.
Res Sq. 2023 Aug 22:rs.3.rs-2924123. doi: 10.21203/rs.3.rs-2924123/v1.
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 observed 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 cell biology analyses, we discovered that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr formed a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhanced Plk4's functionality by promoting its relocalization to the procentriole assembly and induced 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, abrogated Vpr's capacity to induce all these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induced multiple centrosomes and aneuploidy in 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感染会增加患各种癌症的风险，包括T细胞淋巴瘤。HIV-1编码的蛋白质是否直接促成肿瘤发生尚不清楚。我们观察到，来自HIV-1感染者血液中的约1%-5%的CD4 T细胞表现出中心粒过度复制，这表明中心体扩增通过驱动非整倍体而成为HIV-1相关癌症发展的基础。通过亲和纯化、生化和细胞生物学分析，我们发现HIV-1的辅助蛋白Vpr劫持中心粒复制机制，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）形成了一个协同三元复合物。然而，出乎意料的是，该复合物通过促进Plk4重新定位到原中心粒组装部位来增强其功能，并诱导中心体扩增。Vpr的C末端17个残基或VprBP酸性区域的缺失，这两个是与Plk4隐匿性polo盒结合所需的元件，消除了Vpr诱导所有这些事件的能力。此外，HIV-1野生型而非其Vpr突变体在原代CD4 T细胞中诱导多个中心体和非整倍体。我们提出，Vpr•VprBP•Plk4复合物作为一个分子纽带，将HIV-1感染与肿瘤发生联系起来，并且抑制Vpr C末端基序可能会减少HIV-1相关癌症的发生。
