title: Evolutionarily conserved requirement for core binding factor beta in the assembly of the human immunodeficiency virus/simian immunodeficiency virus Vif-cullin 5-RING E3 ubiquitin ligase.
abstract: The human immunodeficiency virus type 1 (HIV-1)-encoded virion infectivity factor (Vif) is required to inactivate the host restriction factor APOBEC3 by engaging Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function; as yet, its mechanism of regulation remains unclear. In the present study, we demonstrate that CBF-β promotion of Vif-CRL5 assembly is independent of its influence on Vif stability and is also a conserved feature of primate lentiviral Vif proteins. Furthermore, CBF-β is critical for the formation of the Vif-ElonginB/ElonginC-Cul5 core E3 ubiquitin ligase complex in vitro. CBF-β from diverse vertebrate species supported HIV-1 Vif function, indicating the conserved nature of Vif-CBF-β interfaces. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
  
  
  OBJECTIVE
  HIV-1 encodes virion infectivity factor (Vif) to inactivate its host's antiviral APOBEC3 proteins. Vif triggers APOBEC3 degradation by forming Vif-Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function whose mechanism of regulation remains poorly defined. In the present study, we demonstrate that the promotion of Vif-CRL5 assembly by CBF-β can be separated from its influence on Vif stability. The promotion of Vif-CRL5 assembly, but not the influence on Vif stability, is conserved among primate lentiviral Vif proteins: we found that CBF-β from diverse vertebrate species supported HIV-1 Vif function. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function and HIV-1 replication, disrupting this interaction is an attractive strategy against HIV-1.
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Weizi
authors.initials: W
authors.lastname: Liang
authors.forename: Deping
authors.initials: D
authors.lastname: Hua
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Sean L
authors.initials: SL
authors.lastname: Evans
authors.forename: Qimeng
authors.initials: Q
authors.lastname: Gao
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Rachel
authors.initials: R
authors.lastname: Viqueira
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D000075065:Elongin; D019143:Evolution, Molecular; D016346:Gene Products, vif / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C496871:CUL5 protein, human; D050658:Core Binding Factor beta Subunit; D044842:Cullin Proteins; D000075065:Elongin; D016346:Gene Products, vif; D014157:Transcription Factors; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases