Death, Destruction, and the Proteasome
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《新英格兰医药杂志》
Apoptosis is an amazing thing. By endowing cells with the ability to kill themselves, nature allows entire organisms to be spared at the expense of a few dysfunctional, damaged, or malignant cells. But this strategy comes at a price — mechanisms must exist to keep the apoptotic machinery inactive under normal conditions and quickly activate it when the cell must die. New work by Sun and colleagues1 reveals that the switch to rapid and efficient cell death unexpectedly involves the destruction of the highest-profile protease within the cell — the 26S proteasome.
Without a doubt, proteolysis is one of the most effective means of regulating protein function. Unlike other forms of regulation, such as phosphorylation and acetylation, proteolysis provides an irreversible and unequivocal way of limiting protein activity. It is therefore not surprising that whenever cells really need to take control of a biologic process, the heavy proteolytic machinery is wheeled out. And it does not get much heavier than the 26S proteasome.
The 26S proteasome is a large (roughly 2.5-MDa), self-compartmentalized protease, which consists of a barrel-shaped 20S particle possessing the proteolytic activities that is capped at one or both ends with a so-called 19S regulatory particle (Figure 1). The architecture of the proteasome generally confines its activity to substrates that have been marked for destruction by prior linkage to the protein ubiquitin. Because protein ubiquitylation is itself a highly specific process, the proteasome is capable of destroying proteins aggressively, but with exquisite substrate specificity. The efficiency and selectivity of proteasomal proteolysis make it effective in controlling a variety of processes, including embryonic development, the cell cycle, and gene expression.
Figure 1. Prodding the Proteasome.
The proteasome both represses and induces apoptosis. When mitochondria receive an apoptotic stimulus, they release cytochrome c and other molecules, which activate the Apaf complex; Smac/Diablo; and other proapoptotic molecules. Initially, the levels of Smac/Diablo are kept low by proteasomal proteolysis. But if sufficient Smac/Diablo is released, some molecules escape destruction by the proteasome and trigger activation of the initiator caspase, caspase 9, as well as effector caspases. A recent study by Sun et al. shows that activated caspases attack and inactivate the proteasome.1 This, in turn, increases Smac/Diablo levels and may result in an even greater activation of the caspases. The study therefore suggests a mechanism by which a recently approved treatment for multiple myeloma (a proteasome inhibitor) may work. The red bars represent inhibition, and the purple arrows activation.
But what does the proteasome have to do with apoptosis? By its very nature, apoptosis demands that normal, healthy cells carry with them all the proteins required for their own death. In good times, these components of the apoptotic machinery must be tightly controlled to prevent premature cell death. The ubiquitin–proteasome system helps to prevent such a catastrophe by destroying a number of key proapoptotic proteins within the cell.2 The rapid and controlled turnover of proapoptotic proteins such as Smac/Diablo3 and Omi/HtrA21 keeps their intracellular levels low, thereby preventing ectopic activation of the apoptotic cascade.
Understandably, therefore, the issue of how the proteasome limits apoptosis has received much attention in recent years. Conceptually, however, this is only half the story. For when the time comes for a cell to die, the safety mechanisms that were in place must be removed, and quickly. The study by Sun et al.1 shows one way in which this can happen and provides an unexpected perspective on some familiar players by showing that the proteasome itself is inactivated during the induction of apoptosis.
In a nutshell, Sun and colleagues demonstrate that three subunits of the 19S particle are cleaved by caspases in response to apoptotic stimuli. Slashed by the caspases, these 19S proteins are unable to recognize (and thus destroy) ubiquitylated substrates. In turn, this inhibition of proteasome function causes ubiquitylated proteins to accumulate and leads to a commensurate spike in the steady-state levels of both Smac/Diablo and Omi/HtrA2 (and probably many other proteins as well). This remarkable feed-forward loop thus not only sets a critical threshold for caspase activation, but also acts potently to amplify the apoptotic signal, ensuring that cells die quickly. This whole process seems to happen early in apoptosis, suggesting that it is not a consequence of everything in the cell simply going to hell, but rather an initiating or amplifying part of the apoptotic cascade.
The ubiquitin–proteasome system is emerging as a major target for therapies designed to battle inflammation and cancer. The proteasome inhibitor bortezomib, for example, was recently and rapidly approved for the treatment of multiple myeloma4 after clinical trials reported promising results that took most basic researchers by surprise. The effectiveness and selectivity of such compounds are not clearly understood, although their ability to promote apoptosis is well documented.5 In the light of the study by Sun et al., perhaps we should be thinking of these compounds (in part, at least) as mimicking caspases, stimulating the caspase–proteasome–Smac/Diablo feed-forward loop, and thus accelerating apoptosis. Indeed, now that we know such a loop exists, it should be possible to design more effective ways of tricking cancer cells into committing suicide.
Source Information
From Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
References
Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM. Caspase activation inhibits proteasome function during apoptosis. Mol Cell 2004;14:81-93.
Zhang HG, Wang J, Yang X, Hsu HC, Mountz JD. Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 2004;23:2009-2015.
MacFarlane M, Merrison W, Bratton SB, Cohen GM. Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem 2002;277:36611-36616.
Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003;8:508-513.
Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071-3076.(William Patrick Tansey, P)
Without a doubt, proteolysis is one of the most effective means of regulating protein function. Unlike other forms of regulation, such as phosphorylation and acetylation, proteolysis provides an irreversible and unequivocal way of limiting protein activity. It is therefore not surprising that whenever cells really need to take control of a biologic process, the heavy proteolytic machinery is wheeled out. And it does not get much heavier than the 26S proteasome.
The 26S proteasome is a large (roughly 2.5-MDa), self-compartmentalized protease, which consists of a barrel-shaped 20S particle possessing the proteolytic activities that is capped at one or both ends with a so-called 19S regulatory particle (Figure 1). The architecture of the proteasome generally confines its activity to substrates that have been marked for destruction by prior linkage to the protein ubiquitin. Because protein ubiquitylation is itself a highly specific process, the proteasome is capable of destroying proteins aggressively, but with exquisite substrate specificity. The efficiency and selectivity of proteasomal proteolysis make it effective in controlling a variety of processes, including embryonic development, the cell cycle, and gene expression.
Figure 1. Prodding the Proteasome.
The proteasome both represses and induces apoptosis. When mitochondria receive an apoptotic stimulus, they release cytochrome c and other molecules, which activate the Apaf complex; Smac/Diablo; and other proapoptotic molecules. Initially, the levels of Smac/Diablo are kept low by proteasomal proteolysis. But if sufficient Smac/Diablo is released, some molecules escape destruction by the proteasome and trigger activation of the initiator caspase, caspase 9, as well as effector caspases. A recent study by Sun et al. shows that activated caspases attack and inactivate the proteasome.1 This, in turn, increases Smac/Diablo levels and may result in an even greater activation of the caspases. The study therefore suggests a mechanism by which a recently approved treatment for multiple myeloma (a proteasome inhibitor) may work. The red bars represent inhibition, and the purple arrows activation.
But what does the proteasome have to do with apoptosis? By its very nature, apoptosis demands that normal, healthy cells carry with them all the proteins required for their own death. In good times, these components of the apoptotic machinery must be tightly controlled to prevent premature cell death. The ubiquitin–proteasome system helps to prevent such a catastrophe by destroying a number of key proapoptotic proteins within the cell.2 The rapid and controlled turnover of proapoptotic proteins such as Smac/Diablo3 and Omi/HtrA21 keeps their intracellular levels low, thereby preventing ectopic activation of the apoptotic cascade.
Understandably, therefore, the issue of how the proteasome limits apoptosis has received much attention in recent years. Conceptually, however, this is only half the story. For when the time comes for a cell to die, the safety mechanisms that were in place must be removed, and quickly. The study by Sun et al.1 shows one way in which this can happen and provides an unexpected perspective on some familiar players by showing that the proteasome itself is inactivated during the induction of apoptosis.
In a nutshell, Sun and colleagues demonstrate that three subunits of the 19S particle are cleaved by caspases in response to apoptotic stimuli. Slashed by the caspases, these 19S proteins are unable to recognize (and thus destroy) ubiquitylated substrates. In turn, this inhibition of proteasome function causes ubiquitylated proteins to accumulate and leads to a commensurate spike in the steady-state levels of both Smac/Diablo and Omi/HtrA2 (and probably many other proteins as well). This remarkable feed-forward loop thus not only sets a critical threshold for caspase activation, but also acts potently to amplify the apoptotic signal, ensuring that cells die quickly. This whole process seems to happen early in apoptosis, suggesting that it is not a consequence of everything in the cell simply going to hell, but rather an initiating or amplifying part of the apoptotic cascade.
The ubiquitin–proteasome system is emerging as a major target for therapies designed to battle inflammation and cancer. The proteasome inhibitor bortezomib, for example, was recently and rapidly approved for the treatment of multiple myeloma4 after clinical trials reported promising results that took most basic researchers by surprise. The effectiveness and selectivity of such compounds are not clearly understood, although their ability to promote apoptosis is well documented.5 In the light of the study by Sun et al., perhaps we should be thinking of these compounds (in part, at least) as mimicking caspases, stimulating the caspase–proteasome–Smac/Diablo feed-forward loop, and thus accelerating apoptosis. Indeed, now that we know such a loop exists, it should be possible to design more effective ways of tricking cancer cells into committing suicide.
Source Information
From Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
References
Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM. Caspase activation inhibits proteasome function during apoptosis. Mol Cell 2004;14:81-93.
Zhang HG, Wang J, Yang X, Hsu HC, Mountz JD. Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 2004;23:2009-2015.
MacFarlane M, Merrison W, Bratton SB, Cohen GM. Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem 2002;277:36611-36616.
Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003;8:508-513.
Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071-3076.(William Patrick Tansey, P)