Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular demise and elucidated several ...of the key cell death pathways. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
Active cell death, in its many forms, is a fundamental biological process, and its study over the past several decades has provided key insights into the molecular processes, functions, and consequences responsible. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
Summary
Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be ...triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best‐known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor‐mediated activation of programmed cell death is the aspartate‐specific cysteine protease (caspase)‐8. This review describes the role of caspase‐8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase‐8 inhibits necroptosis. The importance of caspase‐8 in the development and homeostasis and the way that dysfunctional caspase‐8 may contribute to the development of malignancies in mice and humans are also explored.
Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates with the lysosomal degradation of superfluous or potentially dangerous cytosolic entities. Over ...the past 2 decades, the molecular mechanisms underlying several variants of autophagy have been characterized in detail. Accumulating evidence suggests that most, if not all, components of the molecular machinery for autophagy also mediate autophagy-independent functions. Here, we discuss emerging data on the non-autophagic functions of autophagy-relevant proteins.
Proteins that regulate macroautophagy mediate a number of non-autophagy roles in physiology and disease.
The BCL-2 proteins, named for the first family member to be described (B cell lympho-ma-2), are a collection of related molecules found throughout the animal kingdom. They share only limited sequence ...similarity, except in short regions called BCL-2 homology (BH) domains, and can be grouped according to which of these domains they carry and, as we will see, by their functions. There are three "flavors" of BCL-2 proteins. The pro-apoptotic BCL-2 effectors promote apoptosis by causing mitochondrial outer membrane permeabilization (MOMP). The anti-apoptotic BCL-2 proteins, which include BCL-2 itself, prevent apoptosis by preventing MOMP. The third group is a subfamily of proteins that promote apoptosis by regulating the other two types of BCL-2 molecules.
Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane ...permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.
The health of metazoan organisms requires an effective response to organellar and cellular damage either by repair of such damage and/or by elimination of the damaged parts of the cells or the ...damaged cell in its entirety. Here, we consider the progress that has been made in the last few decades in determining the fates of damaged organelles and damaged cells through discrete, but genetically overlapping, pathways involving the selective autophagy and cell death machinery. We further discuss the ways in which the autophagy machinery may impact the clearance and consequences of dying cells for host physiology. Failure in the proper removal of damaged organelles and/or damaged cells by selective autophagy and cell death processes is likely to contribute to developmental abnormalities, cancer, aging, inflammation, and other diseases.
The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via ...regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc’s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature.
Green focuses on the mitochondrial pathway of apoptosis. The major mode of apoptosis in vertebrates is the mitochondrial pathway. This pathway of cell death is engaged by a vast array of cell ...stresses, including deprivation of growth factors, disruption of the cytoskeleton, DNA damage, accumulation of unfolded proteins, hypoxia, and many others. It is also activated by developmental signals, such as hormones, that instruct cells to die. The author discusses how mitochondria are involved in the activation of caspases in this type of cell death.
Cell Death Signaling Green, Douglas R; Llambi, Fabien
Cold Spring Harbor perspectives in biology,
2015-Dec-01, 2015-12-00, 20151201, Letnik:
7, Številka:
12
Journal Article
Recenzirano
Odprti dostop
In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells. There are three major types of morphologically ...distinct cell death: apoptosis (type I cell death), autophagic cell death (type II), and necrosis (type III). All three can be executed through distinct, and sometimes overlapping, signaling pathways that are engaged in response to specific stimuli. Apoptosis is triggered when cell-surface death receptors such as Fas are bound by their ligands (the extrinsic pathway) or when Bcl2-family proapoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both pathways converge on the activation of the caspase protease family, which is ultimately responsible for the dismantling of the cell. Autophagy defines a catabolic process in which parts of the cytosol and specific organelles are engulfed by a double-membrane structure, known as the autophagosome, and eventually degraded. Autophagy is mostly a survival mechanism; nevertheless, there are a few examples of autophagic cell death in which components of the autophagic signaling pathway actively promote cell death. Necrotic cell death is characterized by the rapid loss of plasma membrane integrity. This form of cell death can result from active signaling pathways, the best characterized of which is dependent on the activity of the protein kinase RIP3.
Necroptosis Linkermann, Andreas; Green, Douglas R
New England journal of medicine/The New England journal of medicine,
01/2014, Letnik:
370, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cell death is regulated by a variety of mechanisms. This review focuses on one of the more recently identified forms of programmed cell death, necroptosis, and its role in normal and disease states. ...This pathway provides new targets for therapeutic intervention.
As early as the mid-19th century, Rudolf Virchow taught that necrosis is a recognizable form of cell death; since then, pathologists have identified necrosis as both a cause and a consequence of disease. A century later, another form of cell death, apoptosis, was defined, and we now understand that this process is driven by a set of molecular mechanisms that “programs” the cell to die. It has often been assumed that necrosis is distinct from apoptosis, in part because of the belief that necrosis is not programmed by molecular events. It is now clear, however, that in some contexts, necrotic . . .
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