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Molecular and Cellular Biology, November 2004, p. 9763-9770, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9763-9770.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Calcium Binding of ARC Mediates Regulation of Caspase 8 and Cell Death{dagger}

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

Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, South Korea

Received 23 April 2004/ Returned for modification 26 May 2004/ Accepted 20 August 2004

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 expression reduced not only cytosolic Ca2+ transients but also cytotoxic effects 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 Ca2+-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.

* Corresponding author. Mailing address: Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryongdong, Bukgu, Gwangju 500-712, South Korea. Phone: 82-62-970-2492. Fax: 82-62-970-2484. E-mail: ykjung{at}gist.ac.kr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD 21224.

Molecular and Cellular Biology, November 2004, p. 9763-9770, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9763-9770.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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