Choosing Death over Degradation

Abstract

Apoptosis, a form of programmed cell death whereby injured or unnecessary cells are eliminated, involves activation of the caspases (a family of proteolytic enzymes). But proteolytic mechanisms can also inhibit apoptosis. The proteasome, which degrades cytosolic proteins, regulates apoptosis by shifting the balance of proapoptotic and antiapoptotic factors: Inhibiting the proteasome stimulates apoptosis in part through the accumulation of proapoptotic proteins (see Preview by Friedman and Xue). Sun et al. found that, in Jurkat T cells or primary human chronic lymphocytic leukemia cells undergoing apoptosis after DNA damage, release of the proapoptotic proteins Smac and Omi from mitochondria was caspase-independent, whereas their subsequent accumulation in the cytoplasm required caspase activity. In cells undergoing apoptosis after inhibition of the proteasome, however, cytosolic accumulation of Smac and Omi was caspase-independent. Using Annexin V labeling to assess apoptosis, the authors showed that, in cells undergoing apoptosis, caspases cleaved three subunits (S1, S5a, and S6′) of the proteasomal regulatory complex. Cells undergoing apoptosis accumulated ubiquitinated proteins, whereas lysate from apoptotic cells showed less effective proteasomal degradation of Smac and of ubiquitin-dependent and ubiquitin-independent proteasomal substrates than did lysate from control cells. Moreover, apoptotic MCF-7 cells lacking caspase-3 did not cleave S1 or S5a and degraded Smac and Omi less effectively than did apoptotic MCF-7 cells that overexpressed caspase-3. Finally, the authors showed that caspase-3 both cleaved and reduced the functional activity of the purified 26 S proteasome. Thus, not only does the proteasome regulate apoptosis, but caspase-dependent proteasomal inactivation early in the apoptotic process reinforces and amplifies the apoptotic signal. X.-M. Sun, M. Butterworth, M. MacFarlane, W. Dubiel, A. Clechanover, G. M. Cohen, Caspase activation inhibits proteasome function during apoptosis. Mol. Cell 14 , 81-93 (2004). [Online Journal] J. Friedman, D. Xue, To live or die by the sword: The regulation of apoptosis by the proteasome. Dev. Cell 6 , 460-461 (2004). [Online Journal]