Vif hijacks CBF-β to degrade APOBEC3G and promote HIV-1 infection

• Published in: Nature (London) Vol. 481; no. 7381; pp. 371 - 375
• Main Authors: JÄGER, Stefanie, DONG YOUNG KIM, MAHON, Cathal, KANE, Joshua, FRANKS-SKIBA, Kathy, CIMERMANCIC, Peter, BURLINGAME, Alma, SALI, Andrej, CRAIK, Charles S, HARRIS, Reuben S, GROSS, John D, KROGAN, Nevan J, HULTQUIST, Judd F, SHINDO, Keisuke, LARUE, Rebecca S, KWON, Eunju, MING LI, ANDERSON, Brett D, YEN, Linda, STANLEY, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 19.01.2012
• Subjects: Affinity Labels; Animals; APOBEC-3G Deaminase; Biological and medical sciences; Core Binding Factor beta Subunit - metabolism; Cullin Proteins - metabolism; Cytidine Deaminase - metabolism; DNA binding proteins; Fundamental and applied biological sciences. Psychology; Gene Knockdown Techniques; Gene Products, vif - metabolism; Genetic aspects; Genetic Complementation Test; Health aspects; HEK293 Cells; HIV infection; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - physiology; Host-Pathogen Interactions; Humans; Jurkat Cells; Macaca mulatta - metabolism; Macaca mulatta - virology; Mass Spectrometry; Microbiology; Models, Biological; Physiological aspects; Protein Binding; Proteolysis; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Risk factors; Simian Immunodeficiency Virus - metabolism; Ubiquitin-proteasome system; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; vif Gene Products, Human Immunodeficiency Virus - metabolism; Virology; Virus Replication; United States; Virus; Retroviridae; Host agent relation; Human immunodeficiency virus; Lentivirus; Pathogenic
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10693

Restriction factors, such as the retroviral complementary DNA deaminase APOBEC3G, are cellular proteins that dominantly block virus replication. The AIDS virus, human immunodeficiency virus type 1 (HIV-1), produces the accessory factor Vif, which counteracts the host's antiviral defence by hijacking a ubiquitin ligase complex, containing CUL5, ELOC, ELOB and a RING-box protein, and targeting APOBEC3G for degradation. Here we reveal, using an affinity tag/purification mass spectrometry approach, that Vif additionally recruits the transcription cofactor CBF-β to this ubiquitin ligase complex. CBF-β, which normally functions in concert with RUNX DNA binding proteins, allows the reconstitution of a recombinant six-protein assembly that elicits specific polyubiquitination activity with APOBEC3G, but not the related deaminase APOBEC3A. Using RNA knockdown and genetic complementation studies, we also demonstrate that CBF-β is required for Vif-mediated degradation of APOBEC3G and therefore for preserving HIV-1 infectivity. Finally, simian immunodeficiency virus (SIV) Vif also binds to and requires CBF-β to degrade rhesus macaque APOBEC3G, indicating functional conservation. Methods of disrupting the CBF-β-Vif interaction might enable HIV-1 restriction and provide a supplement to current antiviral therapies that primarily target viral proteins.