Life's smile, death's grin: Vital functions of apoptosis-executing proteins

Apoptosis is executed by caspases as well as caspase-independent death effectors. Caspases are expressed as inactive zymogens in virtually all animal cells and are activated in cells destined to undergo apoptosis. However, there are many examples where caspase activation is actually required for cellular processes not related to cell death, namely terminal differentiation, activation, proliferation, and cytoprotection. Several caspase-independent death effectors including apoptosis-inducing factor, endonuclease G and a serine protease (Omi/HtrA2) are released from the mitochondrial intermembrane space upon permeabilization of the outer membrane. Such proteins also have important roles in cellular redox metabolism and/or mitochondrial biogenesis. As a general rule, it thus appears that cell-death-relevant proteins, especially those involved in the core of the executing machinery, have a dual function in life and death. This has important implications for pathophysiology. The fact that the building blocks of the apoptotic machinery have normal functions not related to cell death may mean that essential parts of the apoptotic executioner cannot be lost and thus reduces the possibility of oncogenic mutations that block the apoptotic program. Moreover, therapeutic suppression of unwarranted cell death must be designed to target only the lethal (and not the vital) role of death effectors.