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Apoptosis

Life and death in a FLASH

Nature volume 398, pages 756–757 (1999)Cite this article

In some ways, a cell is a bit like a spy. Many spies, at some point in their career, are found out (and have to swallow a cyanide pill), or they may defect and face execution by former colleagues. Likewise, every cell in a multicellular organism can commit suicide (in situations of extreme stress, for instance), or it may be killed when surrounding cells activate specific cell-surface receptors. The basic mechanism of cellular suicide is similar in organisms ranging from the nematode worm to humans. And on page 777of this issue, Imai et al.1 describe a newly discovered — and completely unexpected — mammalian protein that is involved in it.

Cellular suicide, known as programmed cell death or apoptosis, is a tightly controlled mechanism. In the nematode Caenorhabditis elegans, it is dictated by three proteins2. CED-3, the ‘executioner’, belongs to a family of killer proteases known as the caspases. It is activated by interaction with CED-4, but inhibited by CED-9. A similar trinity has been identified in mammals3. Here, Apaf-1 (equivalent to the nematode CED-4), binds to and activates caspase-9, one of the many mammalian CED-3 homologues. Apaf-1 must itself be activated, and this occurs through a conformational change induced by the binding of ATP and cytochrome c. Activated Apaf-1 molecules join together (oligomerize) and, along with the associated caspase-9, form a protein complex dubbed the apoptosome. This provides a platform for caspase-9 activation. The third component of the mammalian trinity is the CED-9 homologue, encoded by members of the Bcl-2 family. These can block activation of caspase-9 by inhibiting the release of cytochrome c or, possibly, by interacting directly with Apaf-1.

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Figure 1: Apoptotic pathways in the nematode and in mammals.

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  1. the Department of Immunohematology, Leiden University Medical Center, Albinusdreef 2a, 2333 AA, Leiden, The Netherlands

    Jan Paul Medema

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  1. Jan Paul Medema
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Medema, J. Life and death in a FLASH. Nature 398, 756–757 (1999). https://doi.org/10.1038/19638

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