E1B 19K Inhibits Fas-mediated Apoptosis through FADD-dependent Sequestration of FLICE

doi:10.1083/jcb.141.5.1255

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© The Rockefeller University Press, 0021-9525/1998//1255 $5.00
The Journal of Cell Biology, Volume 141, Number 5, , 1998 1255-1266

Articles

E1B 19K Inhibits Fas-mediated Apoptosis through FADD-dependent Sequestration of FLICE

Denise Perez^* and Eileen White^*^,^,

^* Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854

E1B 19K, the adenovirus Bcl-2 homologue, is a potent inhibitorof apoptosis induced by various stimuli including Fas and tumornecrosis factor- ${alpha}$ . Fas and TNFR-1 belong to a family of cytokine-activated receptors that share key components in their signaling pathways,Fas-associating protein with death domain (FADD) and FADD-likeinterleukin-1β–converting enzyme (FLICE), to inducean apoptotic response. We demonstrate here that E1B 19K andBcl-x_L are able to inhibit apoptosis induced by FADD, but notFLICE. Surprisingly, apoptosis was abrogated by E1B 19K and Bcl-x_L when FADD and FLICE were coexpressed. Immunofluorescencestudies demonstrated that FADD expression produced large insolubledeath effector filaments that may represent oligomerized FADD.E1B 19K expression disrupted FADD filament formation causingFADD and FLICE to relocalize to membrane and cytoskeletal structureswhere E1B 19K is normally localized. E1B 19K, however, doesnot detectably bind to FADD, nor does it inhibit FADD and FLICEfrom being recruited to the death-inducing signaling complex (DISC) when Fas is stimulated. Thus, E1B 19K may inhibit Fas-mediatedcell death downstream of FADD recruitment of FLICE but upstreamof FLICE activation by disrupting FADD oligomerization andsequestering an essential component of the DISC.

Abbreviations used in this paper: β-gal, β-galactosidase; BRK, baby rat kidney; CMV, cytomegalovirus; DD, death domain; DED, death effector domain; DISC, death-inducing signaling complex; HA, hemagglutinin; ICE, interleukin-1β–convertase enzyme; TNFR-1, tumor necrosis factor receptor-1.

Address all correspondence to Eileen White, Center for AdvancedBiotechnology and Medicine, Rutgers University, 679 Hoes Lane,Piscataway, NJ 08854. Tel.: (732) 235-5329. Fax: (732) 235-5795.E-mail: ewhite{at}mbcl.rutgers.edu

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