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Mechanism of ASC-mediated apoptosis: Bid-dependent apoptosis in type II cells

Oncogene volume 26, pages 1748–1756 (2007)Cite this article

Abstract

Apoptosis-associated speck-like protein containing a CARD (ASC) is an adaptor molecule that mediates apoptotic and inflammatory signals, and implicated in tumor suppression. However, the mechanism of ASC-mediated apoptosis has not been well elucidated. Here, we investigated the molecular mechanisms of ASC-mediated apoptosis in several cell lines using a caspase recruitment domain 12-Nod2 chimeric protein that transduces the signal from muramyl dipeptide into ASC-mediated apoptosis. Experiments using dominant-negative mutants, small-interfering RNAs and peptide inhibitors for caspases indicated that caspase-8 was generally required for ASC-mediated apoptosis, whereas a requirement for caspase-9 depended on the cell type. In addition, caspase-like apoptosis-regulatory protein (CLARP)/Fas-like inhibitor protein, a natural caspase-8 inhibitor, suppressed ASC-mediated apoptosis, and Clarp−/− mouse embryonic fibroblasts were highly sensitive to ASC-mediated apoptosis. Bax-deficient HCT116 cells were resistant to ASC-mediated apoptosis as reported previously, although we failed to observe colocalization of ASC and Bax in cells. Like Fas-ligand-induced apoptosis, the ASC-mediated apoptosis was inhibited by Bcl-2 and/or Bcl-XL in type-II but not type-I cell lines. Bid was cleaved upon ASC activation, and suppression of endogenous Bid expression using small-interfering RNAs in type-II cells reduced the ASC-mediated apoptosis. These results indicate that ASC, like death receptors, mediates two types of apoptosis depending on the cell type, in a manner involving caspase-8.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas (Cancer) from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government and a grant from the Novartis Foundation (Japan) for the Promotion of Science.

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Author notes

  1. M Hasegawa

    Present address: Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA

Authors and Affiliations

  1. Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    M Hasegawa, K Kawase, R Imamura, T Kinoshita & T Suda

  2. Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA

    N Inohara

  3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    W-C Yeh

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  1. M Hasegawa
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  2. K Kawase
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Correspondence to T Suda.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Hasegawa, M., Kawase, K., Inohara, N. et al. Mechanism of ASC-mediated apoptosis: Bid-dependent apoptosis in type II cells. Oncogene 26, 1748–1756 (2007). https://doi.org/10.1038/sj.onc.1209965

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