Conserved and non-conserved features of HIV-1 and SIVagm Vif mediated suppression of APOBEC3 cytidine deaminases.
Human cytidine deaminase APOBEC3C (A3C) acts as a potent inhibitor of SIVagm and can be regulated by both HIV-1 and SIVagm Vif. The mechanism by which Vif suppresses A3C is unknown. In the present study, we demonstrate that both HIV-1 and SIVagm Vif can act in a proteasome-dependent manner to overcome A3C. SIVagm Vif requires the Cullin5-ElonginB-ElonginC E3 ubiquitin ligase for the degradation of A3C as well as the suppression of its antiviral activity. Mutation of a residue critical for the species-specific recognition of human or monkey A3G by HIV-1 Vif or SIVagm Vif in A3C had little effect on HIV-1 or SIVagm Vif-mediated degradation of A3C. Although the amino-terminal region of A3G was not important for Vif-mediated degradation, the corresponding region in A3C was critical. A3C mutants that were competent for Vif binding but resistant to Vif-mediated degradation were identified. These data suggest that primate lentiviral Vif molecules have evolved to recognize multiple host APOBEC3 proteins through distinct mechanisms. However, Cul5-E3 ubiquitin ligase appears to be a common pathway hijacked by HIV-1 and SIV Vif to defeat APOBEC3 proteins. Furthermore, Vif and APOBEC3 binding is not sufficient for target protein degradation indicating an important but uncharacterized Vif function.
Zhang
Wenyan
W
College of Life Science, Jilin University, Changchun 130021, China.
Huang
Michael
M
Wang
Tao
T
Tan
Lindi
L
Tian
Chunjuan
C
Yu
Xianghui
X
Kong
Wei
W
Yu
Xiao-Fang
XF
D000071478:APOBEC Deaminases; D000818:Animals; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism*; D016346:Gene Products, vif / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000378:metabolism; D013045:Species Specificity; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C496871:CUL5 protein, human; D044842:Cullin Proteins; D016346:Gene Products, vif; D054320:vif Gene Products, Human Immunodeficiency Virus; D046988:Proteasome Endopeptidase Complex; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase