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

Oncogene. 2007 Mar 15;26(12):1748-56. doi: 10.1038/sj.onc.1209965. Epub 2006 Sep 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • BH3 Interacting Domain Death Agonist Protein / physiology*
  • Base Sequence
  • CARD Signaling Adaptor Proteins
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cytoskeletal Proteins / physiology*
  • Humans
  • RNA, Small Interfering


  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • PYCARD protein, human
  • RNA, Small Interfering