title: Regulation of Apobec3F and human immunodeficiency virus type 1 Vif by Vif-Cul5-ElonB/C E3 ubiquitin ligase.
abstract: The human cytidine deaminase Apobec3F (h-A3F), a protein related to the previously recognized antiviral factor Apobec3G (h-A3G), has antiviral activity against human immunodeficiency virus type 1 (HIV-1) that is suppressed by the viral protein Vif. The mechanism of HIV-1 Vif-mediated suppression of h-A3F is not fully understood. Here, we demonstrate that while h-A3F, like h-A3G, was able to suppress primate lentiviruses other than HIV-1 (simian immunodeficiency virus from African green monkeys [SIVagm] and Rhesus macaques [SIVmac]), the interaction between Vif proteins and h-A3F appeared to differ from that with h-A3G. H-A3F showed no change in its species specificity against HIV-1 or SIVagm Vif when a negatively charged amino acid was replaced with a lysine at position 128, a residue critical for h-A3G recognition by HIV-1 Vif. However, HIV-1 Vif, but not SIVagm Vif, was able to bind h-A3F and induce its polyubiquitination and degradation through the Cul5-containing E3 ubiquitin ligase. Interference with Cul5-E3 ligase function by depletion of Cul5, through RNA interference or overexpression of Cul5 mutants, blocked the ability of HIV-1 Vif to suppress h-A3F. A BC-box mutant of HIV-1 Vif that failed to recruit Cul5-E3 ligase but was still able to interact with h-A3F failed to suppress h-A3F. Interestingly, interference with Cul5-E3 ligase function or overexpression of h-A3F or h-A3G also increased the stability of HIV-1 Vif, suggesting that like the substrate molecules h-A3F and h-A3G, the substrate receptor protein Vif is itself also regulated by Cul5-E3 ligase. Our results indicate that Cul5-E3 ligase appears to be a common pathway hijacked by HIV-1 Vif to defeat both h-A3F and h-A3G. Developing inhibitors to disrupt the interaction between Vif and Cul5-E3 ligase could be therapeutically useful, allowing multiple host antiviral factors to suppress HIV-1.
authors: Department of Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors: Bindong
authors: B
authors: Liu
authors: Phuong Thi Nguyen
authors: PT
authors: Sarkis
authors: Kun
authors: K
authors: Luo
authors: Yunkai
authors: Y
authors: Yu
authors: Xiao-Fang
authors: XF
authors: Yu
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D016346:Gene Products, vif / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D017958:Lentiviruses, Primate / Q000502:physiology; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus
chemical_list: D000998:Antiviral Agents; C496871:CUL5 protein, human; D044842:Cullin Proteins; D016346:Gene Products, vif; D054320:vif Gene Products, Human Immunodeficiency Virus; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase