title: CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression.
abstract: 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 CBFβ was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBFβ 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-CBFβ holoenzyme forms a well-defined heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBFβ. Heterodimers of CBFβ and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CBFβ 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.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA 94107, USA.
authors: Dong Young
authors: DY
authors: Kim
authors: Eunju
authors: E
authors: Kwon
authors: Paul D
authors: PD
authors: Hartley
authors: David C
authors: DC
authors: Crosby
authors: Sumanjit
authors: S
authors: Mann
authors: Nevan J
authors: NJ
authors: Krogan
authors: John D
authors: JD
authors: Gross
mesh_terms: D000071478:APOBEC Deaminases; D000595:Amino Acid Sequence; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D016384:Consensus Sequence; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D054875:Ubiquitination; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
chemical_list: D023081:CCAAT-Binding Factor; D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase