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

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.

Pubmed ID: 22190037

Authors

  • Jäger S
  • Kim DY
  • Hultquist JF
  • Shindo K
  • LaRue RS
  • Kwon E
  • Li M
  • Anderson BD
  • Yen L
  • Stanley D
  • Mahon C
  • Kane J
  • Franks-Skiba K
  • Cimermancic P
  • Burlingame A
  • Sali A
  • Craik CS
  • Harris RS
  • Gross JD
  • Krogan NJ

Journal

Nature

Publication Data

January 19, 2012

Associated Grants

  • Agency: NIAID NIH HHS, Id: P01 AI090935
  • Agency: NIAID NIH HHS, Id: P01 AI090935
  • Agency: NIGMS NIH HHS, Id: P01 GM091743
  • Agency: NIGMS NIH HHS, Id: P41 GM103481
  • Agency: NCRR NIH HHS, Id: P41RR001614
  • Agency: NIGMS NIH HHS, Id: P50 GM081879
  • Agency: NIGMS NIH HHS, Id: P50 GM081879
  • Agency: NIGMS NIH HHS, Id: P50 GM082250
  • Agency: NIGMS NIH HHS, Id: P50 GM082250
  • Agency: NIGMS NIH HHS, Id: P50 GM082250-05
  • Agency: NIGMS NIH HHS, Id: P50GM081879
  • Agency: NIAID NIH HHS, Id: R01 AI064046
  • Agency: NIAID NIH HHS, Id: T32 AI083196
  • Agency: NCRR NIH HHS, Id: U54 RR022220

Mesh Terms

  • Affinity Labels
  • Animals
  • Core Binding Factor beta Subunit
  • Cullin Proteins
  • Cytidine Deaminase
  • Gene Knockdown Techniques
  • Gene Products, vif
  • Genetic Complementation Test
  • HEK293 Cells
  • HIV Infections
  • HIV-1
  • Host-Pathogen Interactions
  • Humans
  • Jurkat Cells
  • Macaca mulatta
  • Mass Spectrometry
  • Models, Biological
  • Protein Binding
  • Proteolysis
  • Simian immunodeficiency virus
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Virus Replication
  • vif Gene Products, Human Immunodeficiency Virus