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

Author

Listed:
  • Katarzyna A. Skorupka

    (Frederick National Laboratory for Cancer Research)

  • Kazuhiro Matsuoka

    (National Hospital Organization Nagoya Medical Center)

  • Bakar Hassan

    (National Institutes of Health)

  • Rodolfo Ghirlando

    (DHHS)

  • Vanivilasini Balachandran

    (Frederick National Laboratory for Cancer Research)

  • Ting-Hua Chen

    (Okinawa Institute of Science and Technology Graduate University)

  • Kylie J. Walters

    (National Institutes of Health)

  • Celia A. Schiffer

    (University of Massachusetts Chan Medical School)

  • Matthias Wolf

    (Okinawa Institute of Science and Technology Graduate University
    Academia Sinica)

  • Yasumasa Iwatani

    (National Hospital Organization Nagoya Medical Center
    Nagoya University Graduate School of Medicine)

  • Hiroshi Matsuo

    (Frederick National Laboratory for Cancer Research)

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.

Suggested Citation

  • Katarzyna A. Skorupka & Kazuhiro Matsuoka & Bakar Hassan & Rodolfo Ghirlando & Vanivilasini Balachandran & Ting-Hua Chen & Kylie J. Walters & Celia A. Schiffer & Matthias Wolf & Yasumasa Iwatani & Hir, 2025. "HIV-1 vif mediates ubiquitination of the proximal protomer in the APOBEC3H dimer to induce degradation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60984-y
    DOI: 10.1038/s41467-025-60984-y
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