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- Title
Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4<sup>+</sup> T cells.
- Authors
Park, Jung-Eun; Kim, Tae-Sung; Zeng, Yan; Mikolaj, Melissa; Il Ahn, Jong; Alam, Muhammad S.; Monnie, Christina M.; Shi, Victoria; Zhou, Ming; Chun, Tae-Wook; Maldarelli, Frank; Narayan, Kedar; Ahn, Jinwoo; Ashwell, Jonathan D.; Strebel, Klaus; Lee, Kyung S.
- Abstract
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. People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Subjects
ANEUPLOIDY; T cells; C-terminal residues; CELL analysis; UBIQUITIN ligases; TERNARY forms; T cell receptors; GENE amplification
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-46306-8