HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation
Abstract The APOBEC3 family of cytidine deaminases restricts retroviruses like HIV-1 by mutating viral DNA. HIV-1 evades this restriction by producing Vif, which recruits the Cullin-5 (CUL5) E3 ubiquitin ligase complex to promote APOBEC3 degradation. Here we resolve key aspects of this counter-defen...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60984-y |
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| author | Katarzyna A. Skorupka Kazuhiro Matsuoka Bakar Hassan Rodolfo Ghirlando Vanivilasini Balachandran Ting-Hua Chen Kylie J. Walters Celia A. Schiffer Matthias Wolf Yasumasa Iwatani Hiroshi Matsuo |
| author_facet | Katarzyna A. Skorupka Kazuhiro Matsuoka Bakar Hassan Rodolfo Ghirlando Vanivilasini Balachandran Ting-Hua Chen Kylie J. Walters Celia A. Schiffer Matthias Wolf Yasumasa Iwatani Hiroshi Matsuo |
| author_sort | Katarzyna A. Skorupka |
| collection | DOAJ |
| description | Abstract The APOBEC3 family of cytidine deaminases restricts retroviruses like HIV-1 by mutating viral DNA. HIV-1 evades this restriction by producing Vif, which recruits the Cullin-5 (CUL5) E3 ubiquitin ligase complex to promote APOBEC3 degradation. Here we resolve key aspects of this counter-defense mechanism by determining a 3.6 Å cryo-EM structure of chimpanzee APOBEC3H (cpzA3H) in complex with HIV-1 Vif and three components of the CUL5 E3 ligase-CBFβ, EloB, and EloC (VCBC). The structure captures cpzA3H as an RNA-mediated dimer within the cpzA3H-VCBC complex, allowing us to examine the role of dimerization. We find that ubiquitination occurs specifically at two lysine residues on the Vif-proximal protomer, while the distal protomer remains unmodified. The structural model of the active cpzA3H–Vif–CUL5 E3 ligase holoenzyme reveals spatial preferences for ubiquitin transfer to the targeted lysine residues. These findings enhance our understanding of A3H degradation and suggest new antiviral strategies targeting this host-virus interface. |
| format | Article |
| id | doaj-art-115e91a1bde54facbd57e105a06fbfe8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-115e91a1bde54facbd57e105a06fbfe82025-08-20T04:01:35ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-60984-yHIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradationKatarzyna A. Skorupka0Kazuhiro Matsuoka1Bakar Hassan2Rodolfo Ghirlando3Vanivilasini Balachandran4Ting-Hua Chen5Kylie J. Walters6Celia A. Schiffer7Matthias Wolf8Yasumasa Iwatani9Hiroshi Matsuo10Cancer Innovation Laboratory, Frederick National Laboratory for Cancer ResearchClinical Research Center, National Hospital Organization Nagoya Medical CenterProtein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHSCancer Innovation Laboratory, Frederick National Laboratory for Cancer ResearchMolecular Cryo-Electron Microscopy Unit, Okinawa Institute of Science and Technology Graduate UniversityProtein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical SchoolMolecular Cryo-Electron Microscopy Unit, Okinawa Institute of Science and Technology Graduate UniversityClinical Research Center, National Hospital Organization Nagoya Medical CenterCancer Innovation Laboratory, Frederick National Laboratory for Cancer ResearchAbstract The APOBEC3 family of cytidine deaminases restricts retroviruses like HIV-1 by mutating viral DNA. HIV-1 evades this restriction by producing Vif, which recruits the Cullin-5 (CUL5) E3 ubiquitin ligase complex to promote APOBEC3 degradation. Here we resolve key aspects of this counter-defense mechanism by determining a 3.6 Å cryo-EM structure of chimpanzee APOBEC3H (cpzA3H) in complex with HIV-1 Vif and three components of the CUL5 E3 ligase-CBFβ, EloB, and EloC (VCBC). The structure captures cpzA3H as an RNA-mediated dimer within the cpzA3H-VCBC complex, allowing us to examine the role of dimerization. We find that ubiquitination occurs specifically at two lysine residues on the Vif-proximal protomer, while the distal protomer remains unmodified. The structural model of the active cpzA3H–Vif–CUL5 E3 ligase holoenzyme reveals spatial preferences for ubiquitin transfer to the targeted lysine residues. These findings enhance our understanding of A3H degradation and suggest new antiviral strategies targeting this host-virus interface.https://doi.org/10.1038/s41467-025-60984-y |
| spellingShingle | Katarzyna A. Skorupka Kazuhiro Matsuoka Bakar Hassan Rodolfo Ghirlando Vanivilasini Balachandran Ting-Hua Chen Kylie J. Walters Celia A. Schiffer Matthias Wolf Yasumasa Iwatani Hiroshi Matsuo HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation Nature Communications |
| title | HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation |
| title_full | HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation |
| title_fullStr | HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation |
| title_full_unstemmed | HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation |
| title_short | HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation |
| title_sort | hiv 1 vif mediates ubiquitination of the proximal protomer in the apobec3h dimer to induce degradation |
| url | https://doi.org/10.1038/s41467-025-60984-y |
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