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Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria
Yin Guo1, Srinivasa M Srinivasula, Anne Druilhe
1Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Abstract:
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.
Insights
Caspase-2 initiates apoptosis through the mitochondria by releasing cytochrome c. This process is blocked by Bcl-2 and Bcl-xL, indicating caspase-2 is a direct effector of mitochondrial apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Caspase-2 is an early identified caspase, but its apoptotic mechanism is unclear.
- Understanding caspase-2's role is crucial for elucidating cell death pathways.
Purpose of the Study:
- To investigate the mechanism of caspase-2-induced apoptosis.
- To determine if caspase-2 engages the mitochondria-dependent apoptotic pathway.
Main Methods:
- Investigated caspase-2's effect on cytochrome c release.
- Utilized Bcl-2 and Bcl-xL to assess inhibition of cell death.
- Examined caspase-2's activity on Bid and isolated mitochondria.
Main Results:
- Caspase-2 induces the release of cytochrome c and other apoptogenic factors from mitochondria.
- Bcl-2 and Bcl-xL inhibit caspase-2-induced cell death.
- Caspase-2 cleaves Bid and directly triggers mitochondrial factor release, independent of Bid.
Conclusions:
- Caspase-2 directly engages the mitochondria-dependent apoptotic pathway.
- Caspase-2 acts as a direct effector in initiating apoptosis via mitochondrial mechanisms.