Molluscum contagiosum virus inhibitors of apoptosis: The MC159 v-FLIP protein blocks Fas-induced activation of procaspases and degradation of the related MC160 protein.
Molluscum contagiosum virus contains two open reading frames, MC159 and MC160, that encode proteins with death effector domains resembling those of cellular regulators of apoptosis. Previous transfection analyses indicated that the MC159 protein binds to cellular FADD and inhibits Fas-induced cytolysis. For further studies, we inserted the MC159 or MC160 gene into the genome of vaccinia virus that had its own major anti-apoptosis gene deleted. The MC159-expressing virus blocked Fas-induced activation of caspase-3 and -8, degradation of PARP, and cleavage of DNA, whereas the parental vaccinia virus did not. The MC159 protein bound to procaspase-8, in addition to FADD, and was included in a complex with Fas upon receptor activation. Although the MC160 protein associated with FADD and procaspase-8 in co-immunoprecipitation studies, no protection against morphological or biochemical changes associated with Fas-induced apoptosis were discerned and the MC160 protein itself was degraded. Co-expression of MC159, as well as other caspase inhibitors, protected the MC160 protein from degradation, suggesting a functional relationship between the two viral proteins.
Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 20892-0445, USA.
J L
JL
Shisler
B
B
Moss
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D053200:Fas-Associated Death Domain Protein; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008977:Molluscum contagiosum virus / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D014162:Transfection; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics*; D019014:fas Receptor
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; C505533:FADD protein, human; C421307:FAIM protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D014764:Viral Proteins; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases