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

Young Jae Nam, Kartik Mani, Anthony W. Ashton, Chang Fu Peng, Barath Krishnamurthy, Yukihiro Hayakawa, Peiyee Lee, Stanley J. Korsmeyer, Richard N. Kitsis

Research output: Contribution to journalArticle

138 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)901-912
Number of pages12
JournalMolecular Cell
Volume15
Issue number6
DOIs
StatePublished - Sep 24 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Nam, Y. J., Mani, K., Ashton, A. W., Peng, C. F., Krishnamurthy, B., Hayakawa, Y., Lee, P., Korsmeyer, S. J., & Kitsis, R. N. (2004). Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Molecular Cell, 15(6), 901-912. https://doi.org/10.1016/j.molcel.2004.08.020