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. 1997 Feb 18;94(4):1172-6.
doi: 10.1073/pnas.94.4.1172.

Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis

J Bertin  1 , R C Armstrong, S Ottilie, D A Martin, Y Wang, S Banks, G H Wang, T G Senkevich, E S Alnemri, B Moss, M J Lenardo, K J Tomaselli, J I Cohen
Affiliations

Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis

J Bertin et al. Proc Natl Acad Sci U S A. .

Abstract

To identify novel antiapoptotic proteins encoded by DNA viruses, we searched viral genomes for proteins that might interfere with Fas and TNFR1 apoptotic signaling pathways. We report here that equine herpesvirus type 2 E8 protein and molluscum contagiosum virus MC159 protein both show sequence similarity to the death effector domains (DEDs) of the Fas/TNFR1 signaling components FADD and caspase-8. Yeast two-hybrid analysis revealed that E8 protein interacted with the caspase-8 prodomain whereas MC159 protein interacted with FADD. Furthermore, expression of either E8 protein or MC159 protein protected cells from Fas- and TNFR1-induced apoptosis indicating that certain herpesviruses and poxviruses use DED-mediated interactions to interfere with apoptotic signaling pathways. These findings identify a novel control point exploited by viruses to regulate Fas- and TNFR1-mediated apoptosis.

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Figures

Figure 1
Figure 1
EHV-2 E8 and MCV MC159 are DED-containing proteins. E8 and MC159 DEDs are aligned with the DEDs of FADD and caspase-8. Solid black and gray shading indicate identical and conserved residues, respectively. Dots indicate gaps in the sequence to allow optimal alignment.
Figure 2
Figure 2
E8 and MC159 block Fas- and TNFR1-induced apoptosis. HeLa, Jurkat, and MCF7 cells were transfected with the indicated plasmids and treated with either anti-Fas antibody, TNF, or UV-irradiation. (A) HeLa cells were fixed and stained for β-gal expression following treatment and then viewed by phase-contrast microscopy. (B–D) The percentage of viable cells was determined by measuring the number of cells surviving after treatment with various apoptotic inducers compared with the number of cells receiving no treatment.
Figure 3
Figure 3
Model for E8 and MC159 inhibition of Fas and TNFR1 signaling pathways. Fas and TNFR1 cell surface receptors induce apoptosis through the binding of FADD to the prodomain of caspase-8. E8 and MC159 proteins bind to the caspase-8 prodomain and FADD, respectively, and may block Fas- and TNFR1-induced apoptosis by interfering with the ability of pro-caspase-8 to bind to FADD. In contrast, CrmA and P35 antiapoptotic proteins directly inhibit caspase-8 enzymatic activity.
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