No death without life: vital functions of apoptotic effectors

‘Programmed cell death’ (PCD), an expression that was admirably coined by Richard Lockshin in the 1960s,1 is often resolved by apoptosis, a modality of cell death that is defined by characteristic biochemical and morphological features such as chromatin condensation (pyknosis) and nuclear fragmentation (karyorrhexis).2–5 Perhaps, owing to our bilateral symmetry or our intrinsic intellectual limitations, we tend to categorize elements in dualistic terms. According to this one-dimensional and simplistic logic, cell biologists, biochemists and geneticists have assumed that the processes ensuring cell survival and those involved in cell death would rather be diametrically opposed than overlapping. In apparent accord with this conjecture, genetic screens in Caenorhabditis elegans revealed the existence of genes that are required for developmental cell death of the nematode (and hence named ced genes, for ‘C. elegans death’), yet had no discernible function in its ordinary life.6 The concept was born that the apoptotic machinery of C. elegans, as built up by CED-3 (a caspase), CED-4 (an adaptor molecule), CED-9 (a Bcl-2/Bcl-XL ortholog) and EGL-1 (a Bcl-2 homology domain (BH3)-only protein), would solely exist for the regulation and execution of cell death, and would have no important roles in normal life. This concept was tacitly transferred to the mammalian system when effector caspases (i.e. a group of cysteine-aspartyl-proteases that account for the execution of cell death) were presumed to take part only in cell death and not to be involved in any death-unrelated process.7 Similarly, for a long time, it has been assumed that proapoptotic proteins from the Bcl-2 family as well as apoptosis protease-activating factor 1 (Apaf-1) (the mammalian equivalent of CED-4) would play a part only in self-destructive phenomena. During recent years, however, a paradigm shift has occurred as it becomes clear that proteins involved in the induction of apoptosis or in the apoptotic dismantling of cells also exhibit cell death-unrelated functions.8 Indeed, it seems plausible that evolution has not ‘invented’ proapoptotic factors ex nihilo but rather has ‘appropriated’ molecules that already had a function in vital processes (such as adaptation to stress) into the service of PCD. This is the topic of the present review article.