A NOVEL FAMILY OF VIRAL DEATH EFFECTOR DOMAIN-CONTAINING MOLECULES THAT INHIBIT BOTH CD-95-INDUCED AND TUMOR-NECROSIS-FACTOR RECEPTOR-1-INDUCED APOPTOSIS

Molluscum contagiosum virus proteins MC159 and MC160 and the equine he rpesvirus 2 protein E8 share substantial homology to the death effecto r domain present in the adaptor molecule Fas-associated death domain p rotein (FADD) and the initiating death protease FADD-like interleukin- 1 beta-converting enzyme (FLICE) (caspase-8). FADD and FLICE participa te in generating the death signal from both tumor necrosis factor rece ptor-1 (TNFR-1) and the CD-95 receptor, The flow of death signals from TNFR-1 occurs through the adaptor molecule tumor necrosis factor rece ptor associated death domain protein (TRADD) to FADD to FLICE, whereas for CD-95 the receptor directly communicates with FADD and then FLICE , MC159 and E8 inhibited both TNFR-1- and CD-95-induced apoptosis as w ell as killing mediated by overexpression of the downstream adaptors T RADD and FADD, Neither viral molecule, however, inhibited FLICE-induce d killing, consistent with an inhibitory action upstream of the active death protease, These data suggest the existence of a novel strategy employed by viruses to attenuate host immune killing mechanisms, Given that bovine herpesvirus 4 protein E1.1 and Kaposi's sarcoma associate d herpesvirus protein K13 also possess significant homology to the vir al inhibitory molecules MC159, MC160, and E8, it may be that this clas s of proteins is used ubiquitously by viruses to evade host defense.