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Journal of Virology, January 2002, p. 697-706, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.697-706.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Binding of FADD and Caspase-8 to Molluscum Contagiosum Virus MC159 v-FLIP Is Not Sufficient for Its Antiapoptotic Function

Tara L. Garvey,1 John Bertin,1,{dagger} Richard M. Siegel,2 Guang-hua Wang,1,{ddagger} Michael J. Lenardo,2 and Jeffrey I. Cohen1*

Medical Virology Section, Laboratory of Clinical Investigation,1 Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208922

Received 13 July 2001/ Accepted 10 October 2001

Molluscum contagiosum virus (MCV), a member of the human poxvirus family, encodes the MC159 protein that inhibits Fas-, tumor necrosis factor (TNF)-, and TNF-related apoptosis-inducing ligant (TRAIL)-induced apoptosis. We used site-directed mutagenesis to change charged or hydrophobic amino acid residues to alanines to identify regions of MC159 that are critical for protection from apoptosis and for protein-protein interactions. Surprisingly, while MC159 is thought to block apoptosis by binding to Fas-associated death domain (FADD) or caspase-8, several mutants that lost apoptosis blocking activity still bound to both FADD and caspase-8. Mutations in the predicted hydrophobic patch 1 and {alpha}2 regions of both death effector domains (DEDs) within MC159 resulted in loss of the ability to bind to FADD or caspase-8 and to block apoptosis. Amino acid substitutions in the RXDL motif located in the {alpha}6 region of either DED resulted in loss of protection from apoptosis induced by Fas, TNF, and TRAIL and abolished the ability of MC159 to block death effector filament formation. Thus, charged or hydrophobic amino acids in three regions of the MC159 DEDs (hydrophobic patch 1, {alpha}2, and {alpha}6) are critical for the protein’s ability to interact with cellular proteins and to block apoptosis.

* Corresponding author. Mailing address: Laboratory of Clinical Investigation, National Institutes of Health, Bldg. 10, Rm. 11N228, Bethesda, MD 20892. Phone: (301) 496-5265. Fax: (301) 496-7383. E-mail: jcohen{at}niaid.nih.gov.

{dagger} Present address: Millennium Pharmaceuticals, Inc., Cambridge, MA 02139.

{ddagger} Present address: Department of Pathology, NYU Medical Center, New York, NY 10016.

Journal of Virology, January 2002, p. 697-706, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.697-706.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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