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Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis
J Bertin1, R C Armstrong, S Ottilie
1Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
Certain viruses encode proteins that block cell death pathways. Equine herpesvirus type 2 E8 and molluscum contagiosum virus MC159 proteins interfere with Fas and TNFR1 signaling, protecting cells from apoptosis.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Viruses encode proteins to evade host immune responses.
- Apoptosis, or programmed cell death, is a critical host defense mechanism.
- Fas and TNFR1 signaling pathways are key regulators of apoptosis.
Purpose of the Study:
- To identify novel viral antiapoptotic proteins.
- To investigate viral interference with Fas and TNFR1 apoptotic signaling.
Main Methods:
- Bioinformatic search for viral proteins with homology to death effector domains (DEDs).
- Yeast two-hybrid assays to study protein-protein interactions.
- Cell-based assays to assess protection from apoptosis.
Main Results:
- Equine herpesvirus type 2 E8 protein and molluscum contagiosum virus MC159 protein exhibit DED similarity.
- E8 protein interacts with caspase-8 prodomain; MC159 protein interacts with FADD.
- Both viral proteins confer protection against Fas- and TNFR1-induced apoptosis.
Conclusions:
- Herpesviruses and poxviruses utilize DED-mediated interactions to inhibit apoptosis.
- Viruses exploit DED interactions as a novel control point to regulate host cell death pathways.