When Richard Lockshin coined the expression ‘programmed cell death’ (PCD), more than 40 years ago, he modestly and accurately described the unique morphological and biochemical features of a developmental cell-death process that affected the intersegmental muscles of silkmoths. En passage, he developed the important notion that PCD would be controlled by a combination of cell-extrinsic and cell-intrinsic factors, yet would be executed through a plethora of genetically controlled catabolic reactions, from inside of the self-destroying cell. In retrospect, it is hard to believe that Richard did not foresee that his discovery – a mixture of dedicated and inventive bench work and visionary extrapolation – would be one of the major breakthroughs in cell biology of the 20th century. More interestingly, the process he observed was not apoptosis but one of the emerging new mechanisms of PCD, in a story that is now just unfolding. The concept of PCD, as initially formulated by Richard and then extended and applied by a panoply of follow-up studies, is most intriguing because it introduces the notion of constructive death into the science of life, biology. Perhaps this is the reason why there has been a strong tendency in the field, in particular between 1980 and 2000, to envisage two simplistic approaches to the problem. First, there has been a tendency to believe that there would be just one single important PCD mechanism in animals, namely apoptosis. Second, based on the discovery of the Caenorhabditis elegans death (CED) genes, many non-specialists have thought that there would be a sort of specialized device, the ‘apoptotic machinery’, whose building blocks would be exclusively dedicated to the execution of PCD, yet would not have any relevant function in normal life, as if elan vital and elan letal were necessarily opposed and separate entities. Both these (dogmatic) tendencies toward simplification have been broken, and the field is now open again, as open as during the early days when Lockshin translated his microscopic observations into data and concepts. The present special issue of Cell Death Diffferentiation, which celebrates Richard Lockshin’s 70th birthday, perfectly illustrates this regained spirit of freedom. Although apoptosis undoubtedly represents an important modality of PCD in many animal species, there are other forms of PCD that can be distinguished by simple morphological observation. For example, the linker cell of C. elegans succumbs to a PCD that morphologically resembles necrosis and that does not require any among the quintessential apoptotic (CED) genes. Autophagic processes may also play a major role in the development of the mammalian neural tube, although there may be an important cross talk between apoptotic and autophagic pathways. Human cancer cells do not only succumb to classical apoptosis when their DNA is damaged by chemotherapy or radiotherapy but also can die through mitotic catastrophe, a process in which cell death occurs during or after a prolonged mitotic arrest, often in cells that have undergone microor multinucleation. This mitotic catastrophe can lead to secondary apoptosis and necrosis, and it can be debated whether it constitutes a separate entity of cell death. Irrespective of semantic issues, it appears that there is not just one single cell-death program and that cells can die through multiple distinct subroutines. It has become increasingly clear that none of the individual proteins that participate in the major self-destructive events linked to apoptosis, mitochondrial outer-membrane permeabilization (MOMP) and caspase activation, is exclusively dedicated to self-destructive reactions. Rather, all of them also exert some function in normal, death-unrelated processes. Night killers have day jobs. Thus, two archetypical ‘cell death genes’, egl-1 and ced-4, turned out to play a major role in the adaptation of C. elegans cells to starvation and DNA damage, respectively. Mammalian caspases have also many death-unrelated functions, as illustrated for caspase-8 that participates in the activation of T and B lymphocytes, as well as in macrophage differentiation, among other processes. Caspase-12 turns out to be essential for the induction of cytoprotective autophagy in the context of stress affecting the endoplasmic reticulum. Bcl-2-like proteins, which regulate the cell death-associated mitochondrial membrane permeabilization as well as mitochondrial fission, have been discovered to play a cardinal role in synaptic plasticity. The mutation of Itch, an E3 ubiquitin ligase that plays an important role in determining the stability of p73, induces inflammatory lesions as well as lymphoid hyperplasia, illustrating how one single cell-death regulator can affect multiple cellular functions. Finally, phosphatidylserine exposure, one of the cardinal features of apoptotic cell death, may play an important role in conveying anti-inflammatory
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