title: T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction.
abstract: The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1). HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C , which promotes the polyubiquitination and degradation of APOBEC3 substrates. Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes. In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif-CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
authors.affiliation: First Hospital of Jilin University, Institute of Virology and AIDS Research, Changchun, Jilin Province 130021, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Sean L
authors.initials: SL
authors.lastname: Evans
authors.forename: Yunkai
authors.initials: Y
authors.lastname: Yu
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D000071480:APOBEC-3G Deaminase; D002454:Cell Differentiation; D002460:Cell Line; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D047468:Immunoprecipitation; D008958:Models, Molecular; D011485:Protein Binding; D059748:Proteolysis; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C493692:CBFB protein, human; C496871:CUL5 protein, human; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D044842:Cullin Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase