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 observe that approximately 1–5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicate...
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| Format: | Article |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46306-8 |
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| author | Jung-Eun Park Tae-Sung Kim Yan Zeng Melissa Mikolaj Jong Il Ahn Muhammad S. Alam Christina M. Monnie Victoria Shi Ming Zhou Tae-Wook Chun Frank Maldarelli Kedar Narayan Jinwoo Ahn Jonathan D. Ashwell Klaus Strebel Kyung S. Lee |
| author_facet | Jung-Eun Park Tae-Sung Kim Yan Zeng Melissa Mikolaj Jong Il Ahn Muhammad S. Alam Christina M. Monnie Victoria Shi Ming Zhou Tae-Wook Chun Frank Maldarelli Kedar Narayan Jinwoo Ahn Jonathan D. Ashwell Klaus Strebel Kyung S. Lee |
| author_sort | Jung-Eun Park |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a62a5df966d346acae50282c12b35957 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a62a5df966d346acae50282c12b359572025-02-02T12:31:01ZengNature PortfolioNature Communications2041-17232024-03-0115111810.1038/s41467-024-46306-8Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cellsJung-Eun Park0Tae-Sung Kim1Yan Zeng2Melissa Mikolaj3Jong Il Ahn4Muhammad S. Alam5Christina M. Monnie6Victoria Shi7Ming Zhou8Tae-Wook Chun9Frank Maldarelli10Kedar Narayan11Jinwoo Ahn12Jonathan D. Ashwell13Klaus Strebel14Kyung S. Lee15Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Structural Biology, University of Pittsburgh School of MedicineLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthProtein Characterization Laboratory, Frederick National Laboratory for Cancer ResearchLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthHIV Dynamics and Replication Program, National Cancer Institute, National Institutes of HealthCenter for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Structural Biology, University of Pittsburgh School of MedicineLaboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41467-024-46306-8 |
| spellingShingle | Jung-Eun Park Tae-Sung Kim Yan Zeng Melissa Mikolaj Jong Il Ahn Muhammad S. Alam Christina M. Monnie Victoria Shi Ming Zhou Tae-Wook Chun Frank Maldarelli Kedar Narayan Jinwoo Ahn Jonathan D. Ashwell Klaus Strebel Kyung S. Lee Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells Nature Communications |
| title | Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
| title_full | Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
| title_fullStr | Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
| title_full_unstemmed | Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
| title_short | Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells |
| title_sort | centrosome amplification and aneuploidy driven by the hiv 1 induced vpr•vprbp•plk4 complex in cd4 t cells |
| url | https://doi.org/10.1038/s41467-024-46306-8 |
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