title: Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1.
abstract: Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Kvansakul
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Wei
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Fletcher
authors.forename: Simon N
authors.initials: SN
authors.lastname: Willis
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Colman
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000209:etiology / Q000821:virology*; D004351:Drug Resistance; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D051379:Mice; D011485:Protein Binding; D014764:Viral Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C083278:BHRF1 protein, Human herpesvirus 4; D014764:Viral Proteins