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Review
. 2020 Dec 23;10(1):6.
doi: 10.3390/pathogens10010006.

Poxviral Strategies to Overcome Host Cell Apoptosis

Chathura D Suraweera  1 , Mark G Hinds  2 , Marc Kvansakul  1
Affiliations
Review

Poxviral Strategies to Overcome Host Cell Apoptosis

Chathura D Suraweera et al. Pathogens. .

Abstract

Apoptosis is a form of cellular suicide initiated either via extracellular (extrinsic apoptosis) or intracellular (intrinsic apoptosis) cues. This form of programmed cell death plays a crucial role in development and tissue homeostasis in multicellular organisms and its dysregulation is an underlying cause for many diseases. Intrinsic apoptosis is regulated by members of the evolutionarily conserved B-cell lymphoma-2 (Bcl-2) family, a family that consists of pro- and anti-apoptotic members. Bcl-2 genes have also been assimilated by numerous viruses including pox viruses, in particular the sub-family of chordopoxviridae, a group of viruses known to infect almost all vertebrates. The viral Bcl-2 proteins are virulence factors and aid the evasion of host immune defenses by mimicking the activity of their cellular counterparts. Viral Bcl-2 genes have proved essential for the survival of virus infected cells and structural studies have shown that though they often share very little sequence identity with their cellular counterparts, they have near-identical 3D structures. However, their mechanisms of action are varied. In this review, we examine the structural biology, molecular interactions, and detailed mechanism of action of poxvirus encoded apoptosis inhibitors and how they impact on host-virus interactions to ultimately enable successful infection and propagation of viral infections.

Keywords: Bcl-2; apoptosis; pox virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cartoon representation of crystal structures of poxviral encoded Bcl-2 proteins and comparison with cellular Bcl-xL and other viral Bcl-2 structures. (a) Human Bcl-xL (light blue) in complex with Bax BH3 (tv orange) [73]. All helices are labelled as α1-α7/8 and the view is into the canonical ligand binding groove formed by helices α2-α5. (b) EBV BHRF1 (split pea) in complex with Bim BH3 (blue) [45], (c) ASFV A179L (dirty violet) in complex with Bax BH3 [52] (tv orange), (d) VACV F1L (slate) bound to Bak BH3 (yellow) [54], (e) MYXV M11L (red) bound to Bak BH3 (yellow) [37], and (f) DPV022 (wheat) in complex with Bak BH3 (yellow) [74]. The orientations depicted in (b)–(f) are identical to that in (a).
Figure 2
Figure 2
Schematic diagram of the major pathways of apoptosis and the virus encoded effector molecules that modulated them. All major apoptosis inhibition mechanisms utilized by poxviruses are numbered as 1–8. The cellular intrinsic apoptosis pathway is initiated in the event of viral infection, leading to activation of BH3-only proteins in the cytoplasm. These BH3 proteins interact with cellular pro-survival Bcl-2 proteins to neutralize their activity or directly interact with cellular pro-apoptotic Bcl-2 proteins, releasing them to oligomerize at the mitochondrial outer membrane, leading to membrane permeabilization. Release of cytochrome c and other factors from mitochondria activates the downstream events of intrinsic apoptosis such as APAF-1 activation. Virally encoded Bcl-2 proteins mimic the action of cellular pro-survival Bcl-2 proteins to block apoptosis by a variety of mechanisms. (1) VACV F1L interacts with BH3-only proteins to block their activity and subsequent activation of mitochondrial mediated apoptosis. (2) VACV N1L interacts with cellular BH3-only protein Bid to inhibit the downstream activation of apoptosis. (3) VACV F1L/VACV B13 interacts with caspase-9 and suppress the activation of the caspase cascade and subsequent cell death. (4) Poxvirus encoded vTNFRs mimic cellular TNFR1/2 and block the initiation of extrinsic apoptosis. (5) Poxvirus encoded CPXV CrmA/ VACV B13/B22 antagonize active caspase-8 and downstream activation of intrinsic or extrinsic apoptosis. (6) VACV N1L/A46/A49/A52/B14/B15/K7/MC160 inhibit the activation of NF-κB activation, (7) VACV GAAP blocks the Ca2+ efflux from Golgi/ER, and (8) Cu–Zn–SOD encoded by MYXV inhibits the MOMP and subsequent activation of intrinsic apoptosis.
Figure 3
Figure 3
Cartoon representation of different topologies of VACV Bcl-2 homologs. (a) Crystal structure of the dimer formed by VACV F1L (slate) in complex with Bak BH3 (yellow) where α1 helix of one protomer is swapped with α1 helix of a neighboring protomer, (b) dimer interface formed by VACV N1L (beige), where α1 helix of one protomer interact with α6 of the adjacent protomer in crystal contact. (c) Structural superimposition of cartoon tube representation of VACV F1L and VACV N1L as in a view of hydrophobic binding groove made by α2-α5 facing to front. (d) Cartoon representation of A49 (green) and (e) structure of K7 (cyan). Helices are labelled α1–α7 in (a)–(e).
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