Direct inhibition of human APOBEC3 deaminases by HIV-1 Vif independent of the proteolysis pathway

In this study, we elucidate that VβBCC inhibits deamination by A3G, A3F, and A3B, independently of proteasomal degradation. Surprisingly, we discovered that this inhibition for A3G is directly attributed to the interaction between VβBCC and the C-terminal domain of A3G. Previously, it was believed that Vif did not interact with the C-terminal domain. Our findings suggest that inhibiting the interaction between VβBCC and the C-terminal domain, as well as the N-terminal domain known to be targeted for ubiquitination, of A3G may be needed to prevent counteraction by Vif. Significance An accessory protein of HIV-1, Vif, counteracts the antiviral activity of human cytidine deaminase, APOBEC3 (A3), in various ways. We used real-time NMR and uracil DNA glycosylase-based assay to reveal that VβBCC comprising Vif, CBFβ, EloB, EloC, and Cul5 directly inhibits deamination by A3G, A3F, and A3B, independently of ubiquitination and resultant degradation. Then, direct binding of VβBCC to the C-terminal domains of A3G, A3F, and A3B was revealed by NMR, fluorescence anisotropy, and analytical centrifugation. The C-terminal domains of A3G and A3B had long been thought not to interact with Vif. For a prevention of A3G neutralization, inhibition of the interaction of VβBCC with the C-terminal domain may also be important in addition to that with the N-terminal domain.PMID:38115583 | DOI:10.1016/j.bpj.2023.12.015

Source: Biophysical Journal - December 20, 2023 Category: Physics Authors: Keisuke Kamba Li Wan Satoru Unzai Ryo Morishita Akifumi Takaori-Kondo Takashi Nagata Masato Katahira Source Type: research