Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
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 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..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 06. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Kyung [VerfasserIn] |
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| doi: |
10.21203/rs.3.rs-2924123/v1 |
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| 245 | 1 | 0 | |a Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
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| 520 | |a 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 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. | ||
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| 700 | 1 | |a Kim, Tae-Sung |0 (orcid)0000-0001-8592-3848 |4 aut | |
| 700 | 1 | |a Zeng, Yan |4 aut | |
| 700 | 1 | |a Monnie, Christina |4 aut | |
| 700 | 1 | |a Alam, Muhammad |4 aut | |
| 700 | 1 | |a Zhou, Ming |0 (orcid)0000-0002-7460-550X |4 aut | |
| 700 | 1 | |a Mikolaj, Melissa |4 aut | |
| 700 | 1 | |a Maldarelli, Frank |0 (orcid)0000-0002-3062-5250 |4 aut | |
| 700 | 1 | |a Narayan, Kedar |0 (orcid)0000-0001-7982-6494 |4 aut | |
| 700 | 1 | |a Ahn, Jinwoo |0 (orcid)0000-0003-4339-0515 |4 aut | |
| 700 | 1 | |a Ashwell, Jonathan |0 (orcid)0000-0002-7386-8738 |4 aut | |
| 700 | 1 | |a Strebel, Klaus |4 aut | |
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