J. Cell Biol., Volume 141, Number 5, June 1, 1998 1255-1266

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 inhibitor of apoptosis induced by various stimuli including Fas and tumor necrosis factor-. 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-like interleukin-1-converting enzyme (FLICE), to induce an apoptotic response. We demonstrate here that E1B 19K and Bcl-x_L are able to inhibit apoptosis induced by FADD, but not FLICE. Surprisingly, apoptosis was abrogated by E1B 19K and Bcl-x_L when FADD and FLICE were coexpressed. Immunofluorescence studies demonstrated that FADD expression produced large insoluble death effector filaments that may represent oligomerized FADD. E1B 19K expression disrupted FADD filament formation causing FADD and FLICE to relocalize to membrane and cytoskeletal structures where E1B 19K is normally localized. E1B 19K, however, does not detectably bind to FADD, nor does it inhibit FADD and FLICE from being recruited to the death-inducing signaling complex (DISC) when Fas is stimulated. Thus, E1B 19K may inhibit Fas-mediated cell death downstream of FADD recruitment of FLICE but upstream of FLICE activation by disrupting FADD oligomerization and sequestering an essential component of the DISC.

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