Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation.
HIV-1 Vif (viral infectivity factor) protein overcomes the antiviral activity of the DNA deaminase APOBEC3G by targeting it for proteasomal degradation. We report here that Vif targets APOBEC3G for degradation by forming an SCF-like E3 ubiquitin ligase containing Cullin 5 and Elongins B and C (Cul5-EloB-EloC) through a novel SOCS (suppressor of cytokine signaling)-box that binds EloC. Vif binding to EloC is negatively regulated by serine phosphorylation in the BC-box motif of the SOCS-box. Vif ubiquitination is promoted by Cul5 in vitro and in vivo, and requires an intact SOCS-box. Thus, autoubiquitination of Vif occurs within the assembled Vif-Cul5 complex, analogous to F-box proteins that are autoubiquitinated within their SCF (Skp1-Cullin-F-box) complex. These findings suggest mechanisms that regulate the assembly and activity of Cul5 E3 complexes through phosphorylation or autoubiquitination of the SOCS-box protein, and identify interactions between Vif and host cell proteins that may be therapeutic targets.
Mehle
Andrew
A
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Goncalves
Joao
J
Santa-Marta
Mariana
M
McPike
Mark
M
Gabuzda
Dana
D
D000071480:APOBEC-3G Deaminase; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism*; D003564:Cytidine Deaminase; D016346:Gene Products, vif / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D009700:Nucleoside Deaminases; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus
D044842:Cullin Proteins; D016346:Gene Products, vif; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase