title: Vif hijacks CBF-β to degrade APOBEC3G and promote HIV-1 infection.
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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California 94158, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jäger
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Judd F
authors.initials: JF
authors.lastname: Hultquist
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shindo
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: LaRue
authors.forename: Eunju
authors.initials: E
authors.lastname: Kwon
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Brett D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Linda
authors.initials: L
authors.lastname: Yen
authors.forename: David
authors.initials: D
authors.lastname: Stanley
authors.forename: Cathal
authors.initials: C
authors.lastname: Mahon
authors.forename: Joshua
authors.initials: J
authors.lastname: Kane
authors.forename: Kathy
authors.initials: K
authors.lastname: Franks-Skiba
authors.forename: Peter
authors.initials: P
authors.lastname: Cimermancic
authors.forename: Alma
authors.initials: A
authors.lastname: Burlingame
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: John D
authors.initials: JD
authors.lastname: Gross
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
mesh_terms: D000071480:APOBEC-3G Deaminase; D000345:Affinity Labels; D000818:Animals; D050658:Core Binding Factor beta Subunit / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016346:Gene Products, vif / Q000378:metabolism*; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D008253:Macaca mulatta / Q000378:metabolism / Q000821:virology; D013058:Mass Spectrometry; D008954:Models, Biological; D011485:Protein Binding; D059748:Proteolysis; D015302:Simian Immunodeficiency Virus / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D000345:Affinity Labels; C493692:CBFB protein, human; C496871:CUL5 protein, human; D050658:Core Binding Factor beta Subunit; D044842:Cullin Proteins; D016346:Gene Products, vif; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase