Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G.
Cullin-Ring E3 ubiquitin ligases target substrates for ubiquitin-dependent, proteasome-mediated degradation and regulate critical cellular processes. These cullins assemble with cellular substrate receptor proteins through specific adaptor molecules. F-box- and BC-box-containing receptors use Skp1, ElonginB, and ElonginC as adaptors to recruit Cul1/Cul7 and Cul2/Cul5, respectively. At present, the determinants of Cul2 vs. Cul5 specificity for the BC-box-containing receptors are poorly defined. Here, we demonstrate that primate lentiviral Vif (virion infectivity factor) proteins represent previously uncharacterized substrate receptor proteins that contain divergent BC-box motifs. These molecules selectively assemble with a Cul5-E3 ligase to suppress the antiviral activity of autologous cytidine deaminase APOBEC3G. A previously unrecognized Hx5Cx(17-18)Cx(3-5)H motif that is highly conserved among all primate lentiviral Vif proteins was found to be critical for the selective assembly and activity of Vif-Cul5-E3 ligase. Non-primate lentiviral Vif proteins, which lack this HCCH motif, displayed reduced interaction with Cul5. These data suggest that in addition to target protein specificity, substrate receptor proteins play important roles in cullin selection and functional assembly of cullin-Ring E3 ligases. The discovery of these viral substrate receptor molecules that recruit Cul5 through distinct mechanisms from cellular proteins may facilitate the identification of additional cellular factors that regulate cellular functions through Cul5-E3 ligase. Motifs in Vif that are absent from cellular proteins could also be targets for the development of innovative therapeutics.
Luo
Kun
K
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Xiao
Zuoxiang
Z
Ehrlich
Elana
E
Yu
Yunkai
Y
Liu
Bindong
B
Zheng
Shu
S
Yu
Xiao-Fang
XF
D000071480:APOBEC-3G Deaminase; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism*; D003564:Cytidine Deaminase; D000075065:Elongin; D016346:Gene Products, vif / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D017958:Lentiviruses, Primate / Q000378:metabolism*; D008969:Molecular Sequence Data; D009700:Nucleoside Deaminases / Q000378:metabolism*; D010802:Phylogeny; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D044842:Cullin Proteins; D000075065:Elongin; D016346:Gene Products, vif; D012097:Repressor Proteins; D014157:Transcription Factors; D043743:Ubiquitin-Protein Ligase Complexes; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase