14. Apoptosis involves changes at the mitochondrial envelope

27.13 A common pathway for apoptosis functions via caspases

Key terms defined in this section
Caspases comprise a family of protease some of whose members are involved in apoptosis (programmed cell death)



Figure 27.41 Apoptosis can be triggered by activating surface receptors. Caspase proteases are activated at two stages in the pathway. Caspase-8 is activated by the receptor. This leads to release of cytochome c from mitochondria. Apoptosis can be blocked at this stage by Bcl-2. Cytochrome c activates a pathway involving more caspases.

The "classical" pathway for apoptosis is summarized in Figure 27.41. A ligand-receptor interaction triggers the activation of a protease. This leads to the release of cytochrome c from mitochondria. This in turn activates a series of proteases, whose actions culminate in the destruction of cell structures (for review see Budihardjo et al., 1999).




Figure 27.42 The TNF-R1 and Fas receptors bind FADD (directly or indirectly). FADD binds caspase-8. Activation of the receptor causes oligomerization of caspase-8, which activates the caspase.

A complex containing several components forms at the receptor. The exact components of the complex depends on the receptor. TNF receptor binds a protein called TRADD, which in turn binds a protein called FADD. Fas receptor binds FADD directly. Figure 27.42 shows that, in either case, FADD binds the protein caspase-8 (also known as FLICE), which has a death domain as well as protease catalytic activity.The activation of caspase-8 activates a common pathway for apoptosis. The trigger for the activation event is the oligomerization of the receptor. In the case of the Fas system, the interaction of FasL with Fas causes the Fas receptor to trimerize, activating the pathway.


Members of the caspase family (cysteine aspartate proteases) are important downstream components of the pathway. Caspases have a catalytic cysteine, and cleave their targets at an aspartate. Individual enzymes have related, but not identical targets. For example, caspase-3 and ICE both cleave at tetrapeptide sequences in their substrates, but caspase-3 recognizes YVAD and and ICE recognizes DEVD. There are ~12 mammalian members of the caspase family. Several, but not all, are involved in apoptosis.




Figure 27.43 Caspase activation requires dimerization and two cleavages.

Caspases fall into two groups. The caspase-1 subfamily is involved in the response to inflammation. The caspase-3 subfamily (consisting of caspase 3 and caspases 6-10) is involved in apoptosis. All caspases are synthesized in the form of inactive procaspases, which have additional sequences at the N-terminus. Figure 27.43 shows that the activation reaction involves a dimerization, cleavage of the caspase sequence itself into a small subunit and large subunit, and cleavage to remove the prodomain.


Caspases with large prodomains are involved in initiating apoptosis, and the dimerization causes an autocatalytic cleavage that activates the caspase (for review see Earnshaw, Martins, and Kaufmann, 1999). The prodomain of caspase-8 has two death domain motifs that are responsible for its association with the receptor complex. Cleavage to the active form occurs as soon as procaspase-8 is recruited to the receptor complex (1007, 1008).


Caspases with small prodomains function later in the pathway. The first in the series is activated by an autocleavage when it forms an oligomer. Others later in the pathway typically are activated when another caspase cleaves them .


The first caspase to be discovered (ICE=caspase-1) was the IL-1β-converting enzyme, which cleaves the pro-IL-1β precursor into its active form. Although this caspase is usually involved with the inflammatory response, transfection of ICE into cultured cells causes apoptosis. Tthe process is inhibited by CrmA (a product of cowpox virus). All caspases are inhibited by CrmA, although each caspase has a characteristic sensitivity. CrmA inhibits apoptosis triggered in several different ways, which demonstrates that the caspases play an essential role in the pathway, irrespective of how it is initiated. However, it turns out that ICE is not itself the protease commonly involved in apoptosis, because inactivation of the gene for ICE does not block general apoptosis in the mouse. (The ability of ICE to cause apoptosis demonstrates a danger of the transfection assay: overexpression may allow it to trigger apoptosis, although usually it does not do so. But ICE may be needed specifically for apoptosis of one pathway in lymphocytes (Miura et al., 1993).)


This section updated 5-19-2000




Reviews
Budihardjo, I. et al. (1999). Biochemical pathways of caspase activation during apoptosis.. Ann. Rev. Cell Dev. Biol. 15, 269-290.
Earnshaw, W. C. , Martins, L. M. , and Kaufmann, S. H. (1999). Mammalian caspases: structure, activation, substrates, and functions during apoptosis.. Ann. Rev. Biochem 68, 383-424.

Research
Miura, M. et al. (1993). Induction of apoptosis in fibroblasts by IL-1&#szlig;-converting enzyme, a mammalian homologue of the C elegans death gene ced-3. Cell 75, 653-660.



Genes VII
Genes VII
ISBN: B000R0CSVM
EAN: N/A
Year: 2005
Pages: 382

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