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HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation

  1. Author:
    Skorupka,Katarzyna [ORCID]
    Matsuoka, Kazuhiro
    Hassan,Bakar [ORCID]
    Ghirlando, Rodolfo
    Balachandran,Vanivilasini
    Chen, Ting-Hua [ORCID]
    Walters,Kylie [ORCID]
    Schiffer, Celia A [ORCID]
    Wolf, Matthias [ORCID]
    Iwatani, Yasumasa [ORCID]
    Matsuo,Hiroshi [ORCID]

  2. Author Address

    Cancer Innovation Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702, USA., Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan., Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, 20892-0540, USA., Molecular Cryo-Electron Microscopy Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan., Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA., Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan., Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan. yasumasa.iwatani@nnh.go.jp., Department of AIDS Research, Division of Basic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. yasumasa.iwatani@nnh.go.jp., Cancer Innovation Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702, USA. hiroshi.matsuo@nih.gov.,
    1. Year: 2025
    2. Date: Jul 01
    3. Epub Date: 2025 07 01
  2. Journal: Nature Communications
    1. 16
    2. 1
    3. Pages: 5879
  4. Type of Article: Article
  5. Article Number: 5879
  1. 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-CBFß, 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. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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External Sources

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  2. DOI: 10.1038/s41467-025-60984-y
  3. PMID: 40593686
  4. PMCID: PMC12217271
  5. PII : 10.1038/s41467-025-60984-y

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  1. Fiscal Year: FY2024-2025
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