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Homeostatic and pathological cell death can take diverse forms that, when disrupted, can lead to diseases such as cancer and degenerative conditions. For a long time, cell death was thought to occur through apoptosis, which is a programmed event that often confers an advantage to the organism, or through necrosis induced by external factors such as trauma or infection. However, it is now clear that the biological reality is more complex. Various forms of programmed necrosis exist, including necroptosis, and cell death can also occur as a result of autophagy – a process that usually breaks down cellular components to aid cell survival during starvation. This article series highlights the progress that has been made in our understanding of different modes of cell death and autophagy and how they function as both a cell survival and cell death mechanism. Together, these articles highlight the defining features of each pathway, as well as the interplay between different cell death modalities in particular biological contexts.
Recent studies in model organisms uncovered prominent links between autophagy and ageing, suggesting that by removing superfluous or damaged cellular content through lysosomal degradation, autophagy supports tissue and organismal fitness and promotes longevity. Thus, autophagy induction could be considered a strategy to extend lifespan.
The selective degradation of cellular components via chaperone-mediated autophagy (CMA) functions to regulate a wide range of cellular processes, from metabolism to DNA repair and cellular reprogramming. Recent in vivo studies have enabled to dissect key roles of CMA in ageing and ageing-associated disorders such as cancer and neurodegeneration.
Autophagy is a process of cellular self-consumption that promotes cell survival in response to stress. Various human pathologies, including cancer, neurodegeneration and inflammation, have been associated with aberrant autophagy, and recent studies of the mechanisms and regulation of autophagy in higher eukaryotes have suggested new therapeutic possibilities.
Recent studies that combine cell biology, structural and proteomic approaches have unravelled how ubiquitin is conjugated to damaged mitochondria through the PINK1–parkin pathway to promote mitophagy. The findings have revealed links between PINK1–parkin, antigen presentation and neuronal survival and have implications for the understanding of neurological disorders.
Several years after the characterization of the role of receptor-interacting serine/threonine protein kinase 1 (RIPK1) in cell survival, inflammation and disease, RIPK1 was implicated in the regulation of a newly identified type of cell death known as necroptosis. This Timeline article describes the discoveries that shed light on the roles of RIPK1, RIPK3, mixed-lineage kinase domain-like protein (MLKL) and other regulators of necroptosis in controlling cell fate.
Selective autophagy pathways engage selective autophagy receptors (SARs) that identify and bind to cellular cargoes (proteins or organelles) destined for degradation. Recent yeast studies have provided insights into the regulation and mechanisms underlying SAR function. As these mechanisms are conserved from yeast to mammals, it is now possible to formulate general principles of how selectivity during autophagy is achieved.
Autophagy serves to degrade proteins during starvation. Recent progress has illuminated how, during starvation and nutrient repletion, autophagy can mobilize diverse cellular energy and nutrient stores, such as lipids, carbohydrates and iron, to salvage key metabolites that sustain and facilitate core anabolic functions.
The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, p53 can also contribute to cell survival by regulating various metabolic pathways to allow cells to adapt to mild metabolic stresses.
Apoptosis, autophagy and necroptosis are discussed in the context of molecular mechanisms of programmed cell death during development and tissue homeostasis. The signals that dying cells produce can in turn induce the apoptosis or proliferation of neighbouring cells.
Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively. It is now clear that these processes often occur sequentially, and that crosstalk between the signalling pathways regulating them generally enables autophagy to block the induction of apoptosis, whereas apoptosis-associated caspase activation shuts off autophagy.
Cell death research was revitalized by the understanding that necrosis can occur in a regulated and genetically controlled manner. Although necroptosis is the most recognized form of regulated necrosis, other examples of this process have emerged. Understanding how these pathways are interconnected should enable regulated necrosis to be therapeutically targeted.
Interactions on the mitochondrial outer membrane between members of the three subgroups of the BCL-2 protein family set the apoptotic threshold. Recent structural insights into the molecular mechanisms of this commitment to apoptosis are guiding the development of new therapeutics for cancer, and potentially also autoimmune and infectious diseases.
Autophagy was thought to be a purely cytosolic event. However, recent data highlight a role for the nucleus in autophagy regulation, showing that a complex network of histone modifications, microRNAs and transcription factors also control this process.
Receptor-interacting protein (RIP1) is a key upstream regulator of signalling pathways that lead to either inflammation or cell death by apoptosis or necroptosis. Recent evidence indicates that the decision between these pathways is regulated by the ubiquitylation and deubiquitylation of RIP1, which determines its interaction with various ubiquitin-binding proteins.