ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway

Takao Ohtsuka, Hoon Ryu, Yohji A. Minamishima, Salvador Macip, Junji Sagara, Keiichi I. Nakayama, Stuart A. Aaronson, Sam W. Lee

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

The apoptosis-associated speck-like protein (ASC) is an unusual adaptor protein that contains the Pyrin/PAAD death domain in addition to the CARD protein-protein interaction domain1-5. Here, we present evidence that ASC can function as an adaptor molecule for Bax and regulate a p53-Bax mitochondrial pathway of apoptosis. When ectopically expressed, ASC interacted directly with Bax, colocalized with Bax to the mitochondria, induced cytochrome c release with a significant reduction of mitochondrial membrane potential and resulted in the activation of caspase-9, -2 and -3. The rapid induction of apoptosis by ASC was not observed in Bax-deficient cells. We also show that induction of ASC after exposure to genotoxic stress is dependent on p53. Blocking of endogenous ASC expression by small-interfering RNA (siRNA) reduced the apoptotic response and inhibited translocation of Bax to mitochondria in response to p53 or genotoxic insult, suggesting that ASC is required to translocate Bax to the mitochondria. Our findings demonstrate that ASC has an essential role in the intrinsic mitochondrial pathway of apoptosis through a p53-Bax network.

Original languageEnglish
Pages (from-to)121-128
Number of pages8
JournalNature Cell Biology
Volume6
Issue number2
DOIs
Publication statusPublished - 2004 Feb

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Apoptosis
Proteins
Mitochondria
Caspase 2
Caspase 9
Mitochondrial Membrane Potential
Cytochromes c
Small Interfering RNA
DNA Damage

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ohtsuka, T., Ryu, H., Minamishima, Y. A., Macip, S., Sagara, J., Nakayama, K. I., ... Lee, S. W. (2004). ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nature Cell Biology, 6(2), 121-128. https://doi.org/10.1038/ncb1087

ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. / Ohtsuka, Takao; Ryu, Hoon; Minamishima, Yohji A.; Macip, Salvador; Sagara, Junji; Nakayama, Keiichi I.; Aaronson, Stuart A.; Lee, Sam W.

In: Nature Cell Biology, Vol. 6, No. 2, 02.2004, p. 121-128.

Research output: Contribution to journalArticle

Ohtsuka, T, Ryu, H, Minamishima, YA, Macip, S, Sagara, J, Nakayama, KI, Aaronson, SA & Lee, SW 2004, 'ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway', Nature Cell Biology, vol. 6, no. 2, pp. 121-128. https://doi.org/10.1038/ncb1087
Ohtsuka T, Ryu H, Minamishima YA, Macip S, Sagara J, Nakayama KI et al. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nature Cell Biology. 2004 Feb;6(2):121-128. https://doi.org/10.1038/ncb1087
Ohtsuka, Takao ; Ryu, Hoon ; Minamishima, Yohji A. ; Macip, Salvador ; Sagara, Junji ; Nakayama, Keiichi I. ; Aaronson, Stuart A. ; Lee, Sam W. / ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. In: Nature Cell Biology. 2004 ; Vol. 6, No. 2. pp. 121-128.
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