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

Stefanie Jäger, Dong Young Kim, Judd F. Hultquist, Keisuke Shindo, Rebecca S. Larue, Eunju Kwon, Ming Li, Brett D. Anderson, Linda Yen, David Stanley, Cathal Mahon, Joshua Kane, Kathy Franks-Skiba, Peter Cimermancic, Alma Burlingame, Andrej Sali, Charles S. Craik, Reuben S. Harris, John D. Gross, Nevan J. Krogan

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)371-375
Number of pages5
JournalNature
Volume481
Issue number7381
DOIs
StatePublished - Jan 19 2012

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