Abstract:
:Death-fold domains constitute an evolutionarily conserved superfamily that mediates apoptotic signaling. These motifs, including CARD (caspase recruitment domain), DD (death domain), and DED (death effector domain), are believed to exert their effects solely through homotypic interactions. Herein we demonstrate that the CARD-containing protein ARC engages in nontraditional death-fold interactions to suppress both extrinsic and intrinsic death pathways. The extrinsic pathway is disrupted by heterotypic interactions between ARC's CARD and the DDs of Fas and FADD, which inhibit Fas-FADD binding and assembly of the death-inducing signaling complex (DISC). The intrinsic pathway is antagonized by ARC-Bax binding, involving ARC's CARD and the Bax C terminus. This inhibits Bax activation and translocation to the mitochondria. Knockdown of endogenous ARC facilitates DISC assembly and triggers spontaneous Bax activation and apoptosis. Conversely, physiological levels of ARC suppress these events. These studies establish a critical role for nonhomotypic death-fold interactions in the regulation of apoptosis.
journal_name
Mol Celljournal_title
Molecular cellauthors
Nam YJ,Mani K,Ashton AW,Peng CF,Krishnamurthy B,Hayakawa Y,Lee P,Korsmeyer SJ,Kitsis RNdoi
10.1016/j.molcel.2004.08.020subject
Has Abstractpub_date
2004-09-24 00:00:00pages
901-12issue
6eissn
1097-2765issn
1097-4164pii
S1097-2765(04)00482-4journal_volume
15pub_type
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