Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions.
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.
Nam
Young-Jae
YJ
Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Mani
Kartik
K
Ashton
Anthony W
AW
Peng
Chang-Fu
CF
Krishnamurthy
Barath
B
Hayakawa
Yukihiro
Y
Lee
Peiyee
P
Korsmeyer
Stanley J
SJ
Kitsis
Richard N
RN
D000256:Adenoviridae / Q000235:genetics; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002850:Chromatography, Gel; D053418:Death Domain Receptor Signaling Adaptor Proteins; D006801:Humans; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects; D010649:Phenylalanine / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism
C494826:BAX protein, human; C494827:Bax protein, mouse; C494828:Bax protein, rat; D053418:Death Domain Receptor Signaling Adaptor Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D010649:Phenylalanine; D020169:Caspases