Abstract
BackgroundAll lentiviruses except equine infectious anemia virus (EIVA) antagonize antiviral family APOBEC3 (A3) proteins of the host through viral Vif proteins. The mechanism by which Vif of human, simian or feline immunodeficiency viruses (HIV/SIV/FIV) suppresses the corresponding host A3s has been studied extensively.ResultsHere, we determined that bovine immunodeficiency virus (BIV) and maedi-visna virus (MVV) Vif proteins utilize the Cullin (Cul)-ElonginB (EloB)-ElonginC (EloC) complex (BIV Vif recruits Cul2, while MVV Vif recruits Cul5) to degrade Bos taurus (bt)A3Z2-Z3 and Ovis aries (oa)A3Z2-Z3, respectively, via a proteasome-dependent but a CBF-β-independent pathway. Mutation of the BC box in BIV and MVV Vif, C-terminal hydrophilic replacement of btEloC and oaEloC and dominant-negative mutants of btCul2 and oaCul5 could disrupt the activity of BIV and MVV Vif, respectively. While the membrane-permeable zinc chelator TPEN could block BIV Vif-mediated degradation of btA3Z2-Z3, it had minimal effects on oaA3Z2-Z3 degradation induced by MVV Vif, indicating that Zn is important for the activity of BIV Vif but not MVV Vif. Furthermore, we identified a previously unreported zinc binding loop [C-x1-C-x1-H-x19-C] in the BIV Vif upstream BC box which is critical for its degradation activity.ConclusionsA novel zinc binding loop was identified in the BIV Vif protein that is important for the E3 ubiquination activity, suggesting that the degradation of btA3Z2-Z3 by BIV and that of oaA3Z2-Z3 by MVV Vif may need host factors other than CBF-β.
Highlights
All lentiviruses except equine infectious anemia virus (EIVA) antagonize antiviral family APOBEC3 (A3) proteins of the host through viral viral infectivity factor (Vif) proteins
Studies in recent years have shown that bovine immunodeficiency virus (BIV) and maedi-visna virus (MVV) Vifs can degrade btA3Z2-Z3 and oaA3Z2-Z3, respectively, which allows for effective infection by the corresponding virus (BIV or MVV)
MG132 blocked the degradation of btA3Z2-Z3 and stabilized the BIV Vif protein (Figure 1A, lane 4), implying that the degradation of btA3Z2-Z3 protein depends on proteasome activity similar to Human immunodeficiency virus type 1 (HIV-1) Vif
Summary
All lentiviruses except equine infectious anemia virus (EIVA) antagonize antiviral family APOBEC3 (A3) proteins of the host through viral Vif proteins. HIV-1 Vif antagonizes the antiviral activity of the cellular protein A3G by recruiting the transcription cofactor CBF-β and ElonginB (EloB)-ElonginC (EloC) to the Cullin (Cul5)Rbx complex to degrade A3G [3,12,13,14,15,16,17,18]. The H-x5-C-x17– 18-C-x3 –5-H motif (i.e., HCCH zinc finger) and the PPLPx4L motif ( known as the Cul box) in the C-terminal region of HIV-1 Vif mediate selective binding to Cul5 [24,25,26] Another C-terminal SLQ(Y/F) LA motif (BC box) downstream of the HCCH domain binds with EloC to assemble the E3 ligase complex [12,27,28]. SIVmac239 Vif recruits the transcription cofactor CBF-β and EloB-EloC to the Cul5-Rbx complex, forming the CBF-β-Cul5-EloBEloC E3 ubiquitin ligase to degrade the cellular antiviral protein A3G [29,30]. FIV Vif interacts with feline Cul, EloB and EloC to form an E3 complex to induce degradation of fA3s [31]
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