Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
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.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Nature communications - 15(2024), 1 vom: 05. März, Seite 2017 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Park, Jung-Eun [VerfasserIn] |
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Date Completed 07.03.2024 Date Revised 26.04.2024 published: Electronic UpdateOf: Res Sq. 2023 Aug 22;:. - PMID 37645926 Citation Status MEDLINE |
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| doi: |
10.1038/s41467-024-46306-8 |
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NLM369332059 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Zeng, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Mikolaj, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Il Ahn, Jong |e verfasserin |4 aut | |
| 700 | 1 | |a Alam, Muhammad S |e verfasserin |4 aut | |
| 700 | 1 | |a Monnie, Christina M |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Chun, Tae-Wook |e verfasserin |4 aut | |
| 700 | 1 | |a Maldarelli, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Narayan, Kedar |e verfasserin |4 aut | |
| 700 | 1 | |a Ahn, Jinwoo |e verfasserin |4 aut | |
| 700 | 1 | |a Ashwell, Jonathan D |e verfasserin |4 aut | |
| 700 | 1 | |a Strebel, Klaus |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Kyung S |e verfasserin |4 aut | |
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