Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions

被引:161
作者
Nam, YJ
Mani, K
Ashton, AW
Peng, CF
Krishnamurthy, B
Hayakawa, Y
Lee, P
Korsmeyer, SJ
Kitsis, RN
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA
[3] Yeshiva Univ Albert Einstein Coll Med, Cardiovasc Res Ctr, Bronx, NY 10461 USA
[4] Yeshiva Univ Albert Einstein Coll Med, Ctr Canc, Bronx, NY 10461 USA
[5] Harvard Univ, Sch Med, Howard Hughes Med Inst, Program Mol Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA
[6] Harvard Univ, Dept Pathol, Boston, MA 02115 USA
[7] Harvard Univ, Dept Med, Boston, MA 02115 USA
关键词
D O I
10.1016/j.molcel.2004.08.020
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Death-fold domains constitute an evolutionarily conserved superfamily that mediates apoptotic signaling. These motifs, including CARD (caspase recruitment domain), DID (death domain), and DIED (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.
引用
收藏
页码:901 / 912
页数:12
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