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Title: Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival.
Authors: Hughes, MA
Harper, N
Butterworth, M
Cain, K
Cohen, GM
MacFarlane, M
First Published: 14-Aug-2009
Citation: MOL CELL, 2009, 35 (3), pp. 265-279
Abstract: The death-inducing signaling complex (DISC) is critical for initiation of death-receptor-mediated apoptosis; however, paradoxically, CD95 also signals for cell survival. Here, we reconstitute a functional DISC using only purified CD95, FADD, and procaspase-8 and unveil a two-step activation mechanism involving both dimerization and proteolytic cleavage of procaspase-8 that is obligatory for death-receptor-induced apoptosis. Initially, dimerization yields active procaspase-8 with a very restricted substrate repertoire, limited to itself or c-FLIP. Proteolytic cleavage is then required to fully activate caspase-8, thereby permitting DISC-mediated cleavage of the critical exogenous apoptotic substrates, caspase-3 and Bid. This switch in catalytic activity and substrate range is a key determinant of DISC signaling, as cellular expression of noncleavable procaspase-8 mutants, which undergo DISC-mediated oligomerization, but not cleavage, fails to initiate CD95-induced apoptosis. Thus, using the reconstituted DISC, we have delineated a crucial two-step activation mechanism whereby activated death receptor complexes can trigger death or survival.
DOI Link: 10.1016/j.molcel.2009.06.012
eISSN: 1097-4164
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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