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Review
. 2017 Aug 8;9(8):215.
doi: 10.3390/v9080215.

Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

Daniel Brian Nichols  1 , William De Martini  2 , Jessica Cottrell  3
Affiliations
Review

Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

Daniel Brian Nichols et al. Viruses. .

Abstract

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence.

Keywords: Molluscum Contagiosum Virus; Myxoma Virus; Vaccinia Virus; apoptosis; caspase; host defense; immune evasion; mitochondrial membrane permeabilization; poxvirus; protein kinase R.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Overview of the extrinsic and intrinsic apoptotic pathways. (1) Tumor necrosis factor α (TNFα) or the Fas ligand (FasL) bind to the respective TNF-receptor (TNFR)-1 or FasR receptors. Fas-associated death domain protein (FADD) binds to the cytoplasmic region of FasR and forms a scaffold that recruits procaspase-8.For TNF, TNFR-associated death domain protein (TRADD) associates with the cytoplasmic death domain (DD) of the TNF-R1 and forms complex 1 which leads to nuclear factor κB (NF-κB) activation; (2) Alternatively, TNF can induce apoptosis when receptor-interacting protein 1 (RIP1) forms a cytoplasmic complex II consisting of RIP1, FADD, and procaspase-8; (3) Procaspase-8 oligomerization results in its autocleavage and activation where the initiator caspase-8 activates (4) caspase-3 or cleave additional substrates such as (5) BH3 interacting-doain death agonist (Bid) to truncated (t)Bid; (6) tBid activates Bcl-2 homologous antagonist killer (Bak)/Bcl-2-associated X protein (Bax) oligomers in the mitochondria. Alternatively, Bak/Bax can form pores in the mitochondria outer membrane in response to Ca2+ efflux from the endoplasmic reticulum (ER) or Golgi; (7) Bax/Bak pores result in mitochondria membrane permeabilization which leads to the subsequent release of cytochrome c and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein with low pI) (Smac/DIABLO, referred to as “Smac” in the illustration) from the inner membrane space of the mitochondria to the cytosol; (8) Cytoplasmic cytochrome c binds Apaf1 leading to the formation of the apoptosome and the activation of initiator caspase-9; (9) caspase-9 in turn activates effector caspases such as caspase-3.Smac released form the mitochondria also binds inhibitor of apoptosis proteins (IAPs) which allows caspase-3 to become active and cleave target proteins; (10) Effector caspases in turn cleave target proteins resulting in the activation of apoptosis. Poxvirus proteins are indicated in the open boxes. Red lines indicate points in the pathway inhibited by viral proteins. Vaccinia virus (VACV) F1, Myxoma virus (MYXV) M11, MYXV M131, Shope Fibroma Virus (SFV) S131, and Molluscum Contagiosum Virus (MCV) MC163 localize to the mitochondria where these proteins antagonize mitochondria mediated responses in the intrinsic apoptotic pathway. MYXV M131/SFV S131 are depicted interacting with cellular copper chaperones for superoxide dismutase (CCS).
Figure 2
Figure 2
Viral double stranded RNA (dsRNA) activates protein kinase R (PKR). Upon binding dsRNA, PKR becomes activated and elicits several antiviral responses. Active PKR phosphorylates eukaryotic initiation factor 2α (eIF2α) resulting in inhibition of protein translation. PKR can also mediate apoptosis and NF-κB activation. Several poxvirus proteins inhibit PKR activation using a variety of mechanisms. The red lines indicate points in the pathway targeted by several poxvirus immune evasion molecules.
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References

    1. Gartner A., Milstein S., Ahmed S., Hodgkin J., Hengartner M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell. 2000;5:435–443. doi: 10.1016/S1097-2765(00)80438-4. - DOI - PubMed
    1. Garcia-Calvo M., Peterson E.P., Leiting B., Ruel R., Nicholson D.W., Thornberry N.A. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 1998;273:32608–32613. doi: 10.1074/jbc.273.49.32608. - DOI - PubMed
    1. Fuchs Y., Steller H. Programmed cell death in animal development and disease. Cell. 2011;147:742–758. doi: 10.1016/j.cell.2011.10.033. - DOI - PMC - PubMed
    1. Thornberry N.A., Lazebnik Y. Caspases: Enemies within. Science. 1998;281:1312–1316. doi: 10.1126/science.281.5381.1312. - DOI - PubMed
    1. Nakajima Y.I., Kuranaga E. Caspase-dependent non-apoptotic processes in development. Cell Death Differ. 2017;28:1422–1430. doi: 10.1038/cdd.2017.36. - DOI - PMC - PubMed

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