The HIV-1 accessory protein Vif hijacks a cellular Cullin-RING ubiquitin ligase, CRL5, to promote degradation of the APOBEC3 (A3) family of restriction factors. Recently, the cellular transcription cofactor CBFß was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBFß is required for assembling a well-ordered CRL5-Vif complex by inhibiting Vif oligomerization and by activating CRL5-Vif via direct interaction. The CRL5-Vif-CBFß holoenzyme forms a well-defined heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBFß. Heterodimers of CBFß and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CBFß is mutually exclusive with RUNX heterodimerization and impacts the expression of genes whose regulatory domains are associated with RUNX1. Our results provide a mechanism by which a pathogen with limited coding capacity uses one factor to hijack multiple host pathways.
CCAAT-Binding Factor/metabolism , Core Binding Factor Alpha 2 Subunit/metabolism , Cytosine Deaminase/metabolism , Gene Expression Regulation , vif Gene Products, Human Immunodeficiency Virus/metabolism , APOBEC Deaminases , Amino Acid Sequence , Base Sequence , CCAAT-Binding Factor/chemistry , CCAAT-Binding Factor/physiology , Consensus Sequence , Core Binding Factor Alpha 2 Subunit/chemistry , Core Binding Factor Alpha 2 Subunit/physiology , Cytidine Deaminase , Cytosine Deaminase/chemistry , Cytosine Deaminase/physiology , Gene Expression , Genes, Reporter , HEK293 Cells , HIV-1/physiology , Host-Pathogen Interactions , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization , Protein Processing, Post-Translational , Protein Stability , Protein Structure, Quaternary , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Ubiquitination , vif Gene Products, Human Immunodeficiency Virus/chemistry , vif Gene Products, Human Immunodeficiency Virus/physiology
