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Requirement of cooperative functions of two repeated death effector domains in caspase‐8 and in MC159 for induction and inhibition of apoptosis, respectively
Author(s) -
Tsukumo Shinichi,
Yonehara Shin
Publication year - 1999
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.1999.00280.x
Subject(s) - biology , effector , apoptosis , microbiology and biotechnology , caspase , programmed cell death , immunology , genetics
Background The death effector domain (DED), which functions as a domain for a homophilic protein interaction, plays a role in death receptor‐mediated apoptosis. Two tandemly repeated DEDs in the prodomain of caspase‐8 (Casp8NC‐DED) and those in MC159 (viral FLIP) have been shown to positively and negatively regulate apoptosis, respectively, by binding to caspase‐8 and/or F as‐ a ssociated d eath d omain (FADD). However, characteristics of each DED in Casp8NC‐DED and those in MC159 have not been well examined. Results We analysed deletion and chimera mutants of DEDs derived from Casp8NC‐DED and MC159, and found that MC159 and Casp8NC‐DED require the combined effects of the two repeated DEDs to exert their binding and biological activities. The carboxy‐terminal DED of Casp8NC‐DED (Casp8C‐DED) has the potential to induce apoptosis, and the amino‐terminal DED of MC159 showed a dominant inhibitory effect on apoptosis when combined with Casp8C‐DED. In addition, the two repeated DEDs in Casp8NC‐DED and MC159 were shown to regulate the activities of caspase differently from the caspase recruitment domain (CARD) in the prodomains of caspase‐2, ‐9 and Apaf‐1. Conclusions Although each of the DEDs in Casp8NC‐DED and MC159 has the potential to stimulate or inhibit apoptosis, the combination of the two‐repeated DEDs is necessary for the DED‐containing proteins to stimulate or inhibit apoptosis.