The Bcl-2 Family in Host-Virus Interactions

Abstract

Members of the B cell lymphoma-2 (Bcl-2) family are pivotal arbiters of mitochondrially mediated apoptosis, a process of fundamental importance during tissue development, homeostasis, and disease. At the structural and mechanistic level, the mammalian members of the Bcl-2 family are increasingly well understood, with their interplay ultimately deciding the fate of a cell. Dysregulation of Bcl-2-mediated apoptosis underlies a plethora of diseases, and numerous viruses have acquired homologs of Bcl-2 to subvert host cell apoptosis and autophagy to prevent premature death of an infected cell. Here we review the structural biology, interactions, and mechanisms of action of virus-encoded Bcl-2 proteins, and how they impact on host-virus interactions to ultimately enable successful establishment and propagation of viral infections.

Keywords: Bcl-2; adenovirus; apoptosis; asfarvirus; autophagy; herpesvirus; host-pathogen interactions; iridovirus; poxvirus; structural biology.

Figure 1

Pathways for Bcl-2 protein action. In mammals, a tripartite mechanism regulated by the Bcl-2 family controls the integrity of the mitochondrial outer membrane (MOM). Activation of Bax and Bak leads to MOM permeabilisation (MOMP), and escape of factors such as cytochrome c from the mitochondrial intermembrane space to initiate the caspase cascade that is the defining step in apoptosis. BH3-only proteins either activate Bax and/or Bak either by removal of their inhibition by pro-survival proteins, or by direct interaction. The BH3-only protein Bid is activated by proteolytic cleavage that releases its BH3-motif for interaction. Viral Bcl-2 (vBcl-2) orthologues can act on the BH3-only proteins, or directly block the action of Bax and Bak to prevent apoptosis initiation. Activation steps are shown as arrows and inhibition as bars.

Figure 2

Structures of Bcl-2 family members. (A) Human Bcl-x_L:Bim complex [33] (PDB ID 1PQ1); (B) G. cydonium BHP2:LB-Bak-2 complex [32] (PDB ID 5TWA); (C) EBV BHRF1:Bim complex [34] (PDB ID 2WH6); (D) Myxomavirus M11L:Bak complex [35] (PDB ID 2JBY); (E) African swine fever virus A179L:Bid complex [36] (PDB ID 5UA4); (F) Murine γ-herpesvirus 68 M11:Beclin-1 complex [37] (PDB ID 3BL2); (G) Vaccinia virus F1L:Bim complex [38] (PDB ID 4D2M); (H) Vaccinia virus A52 [39] (PDB ID 2VVW).