TY - JOUR
T1 - Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions
AU - Nam, Young Jae
AU - Mani, Kartik
AU - Ashton, Anthony W.
AU - Peng, Chang Fu
AU - Krishnamurthy, Barath
AU - Hayakawa, Yukihiro
AU - Lee, Peiyee
AU - Korsmeyer, Stanley J.
AU - Kitsis, Richard N.
N1 - Funding Information:
We are indebted to Drs. Gabriel Nunez and Michael T. Crow for reagents, ARIAD Pharmaceuticals for the FKBP homodimerization kit, Drs. Michael T. Crow, Gabriel Nunez, and Yigong Shi for helpful advice, and Dr. Bernardo Nadal-Ginard for insightful comments on the manuscript. This study was funded by National Institutes of Health grants HL60665 and HL61550 (to R.N.K.). R.N.K. was also supported by The Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease of the Albert Einstein College of Medicine and the Monique Weill-Caulier Career Scientist Award. Y.-J.N. was supported by a National Institutes of Health Training Grant in Cellular and Molecular Biology and Genetics (GM 07491).
PY - 2004/9/24
Y1 - 2004/9/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=4644354531&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2004.08.020
DO - 10.1016/j.molcel.2004.08.020
M3 - Article
C2 - 15383280
AN - SCOPUS:4644354531
SN - 1097-2765
VL - 15
SP - 901
EP - 912
JO - Molecular cell
JF - Molecular cell
IS - 6
ER -