Calcium binding of ARC mediates regulation of caspase 8 and cell death

Dong Gyu Jo, Joon Il Jun, Jae Woong Chang, Yeon Mi Hong, Sungmin Song, Dong Hyung Cho, Mi Shim Sang, Ho June Lee, Chunghee Cho, Han Kim Do, Yong Keun Jung

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Apoptosis repressor with CARD (ARC) possesses the ability not only to block activation of caspase 8 but to modulate caspase-independent mitochondrial events associated with cell death. However, it is not known how ARC modulates both caspase-dependent and caspase-independent cell death. Here, we report that ARC is a Ca2+-dependent regulator of caspase 8 and cell death. We found that in Ca2+ overlay and Stains-all assays, ARC protein bound to Ca2+ through the C-terminal proline/glutamate-rich (P/E-rich) domain. ARC expres-sion reduced not only cytosolic Ca2+ transients but also cytotoxic efects of thapsigargin, A23187, and ionomycin, for which the Ca2+-binding domain of ARC was indispensable. Conversely, direct interference of endogenous ARC synthesis by targeting ARC enhanced such Ca 2+-mediated cell death. In addition, binding and immunoprecipitation analyses revealed that the protein-protein interaction between ARC and caspase 8 was decreased by the increase of Ca2+ concentration in vitro and by the treatment of HEK293 cells with thapsigargin in vivo. Caspase 8 activation was also required for the thapsigargin-induced cell death and suppressed by the ectopic expression of ARC. These results suggest that calcium binding mediates regulation of caspase 8 and cell death by ARC.

Original languageEnglish (US)
Pages (from-to)9763-9770
Number of pages8
JournalMolecular and cellular biology
Volume24
Issue number22
DOIs
StatePublished - Nov 2004

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