Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria

J Biol Chem. 2002 Apr 19;277(16):13430-7. doi: 10.1074/jbc.M108029200. Epub 2002 Feb 6.


Caspase-2 is one of the earliest identified caspases, but the mechanism of caspase-2-induced apoptosis remains unknown. We show here that caspase-2 engages the mitochondria-dependent apoptotic pathway by inducing the release of cytochrome c (Cyt c) and other mitochondrial apoptogenic factors into the cell cytoplasm. In support of these observations we found that Bcl-2 and Bcl-xL can block caspase-2- and CRADD (caspase and RIP adaptor with death domain)-induced cell death. Unlike caspase-8, which can process all known caspase zymogens directly, caspase-2 is completely inactive toward other caspase zymogens. However, like caspase-8, physiological levels of purified caspase-2 can cleave cytosolic Bid protein, which in turn can trigger the release of Cyt c from isolated mitochondria. Interestingly, caspase-2 can also induce directly the release of Cyt c, AIF (apoptosis-inducing factor), and Smac (second mitochondria-derived activator of caspases protein) from isolated mitochondria independent of Bid or other cytosolic factors. The caspase-2-released Cyt c is sufficient to activate the Apaf-caspase-9 apoptosome in vitro. In combination, our data suggest that caspase-2 is a direct effector of the mitochondrial apoptotic pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein
  • CRADD Signaling Adaptor Protein
  • Carrier Proteins / metabolism
  • Caspase 2
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cytochrome c Group / metabolism
  • Cytoplasm / enzymology
  • Cytosol / enzymology
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Protein Structure, Tertiary
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Recombinant Proteins / metabolism
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • bcl-X Protein


  • Adaptor Proteins, Signal Transducing
  • BCL2L1 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • bcl-X Protein
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 2
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases