Caspase-8: regulating life and death.
TL;DR: The role of caspase‐8 in the initiation of extrinsic apoptosis execution and the mechanism by which casp enzyme‐8 inhibits necroptosis are described.
Abstract: 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.
Citations
More filters
TL;DR: Current understanding of caspase biology is reviewed with a prime focus on the inflammatory caspases and important topics for future experimentation are outlined.
582 citations
TL;DR: The evidence implicating necroptosis in neurological diseases is outlined and it is suggested that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
Abstract: Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
451 citations
TL;DR: Despite necroptosis being challenging to detect in vivo, there is accumulating evidence that this cell death form is a pathogenically relevant driver in several liver diseases that were associated with apoptosis.
Abstract: Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications
308 citations
TL;DR: The mechanisms of efferocytosis are outlined, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and the pathophysiological consequences that can arise when this process is abrogated are highlighted.
Abstract: Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other 'professional' phagocytes (such as monocytes and dendritic cells) and 'non-professional' phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.
303 citations
TL;DR: It is reported that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells, which may lead to the lung damage in the COVID-19 patients.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.
244 citations
References
More filters
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.
Abstract: The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.
15,416 citations
TL;DR: The characterization of an inhibitor of apoptosis is reported, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues and may be implicated in tissue homeostasis as an important regulator of apoptotic regulation.
Abstract: The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis1 However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals1,2, indicating that inhibitors of the apoptosis-signalling pathway must exist Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues The short form, FLIPS, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis3, whereas the long form, FLIPL, contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue FLIPS and FLIPL interact with the adaptor protein FADD4,5 and the protease FLICE6,7, and potently inhibit apoptosis induced by all known human death receptors1 FLIPL is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis High levels of FLIPL protein are also detectable in melanoma cell lines and malignant melanoma tumours Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis
2,639 citations
TL;DR: Findings indicate that Caspase 8 plays a necessary and nonredundant role in death induction by several receptors of the TNF/NGF family and serves a vital role in embryonal development.
1,228 citations
TL;DR: It is found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL, also known as CFLAR), and this complex is required for the protective function.
Abstract: Caspase-8 mediates apoptosis induced by 'death receptors' on the cell's surface. At the same time, it is able to prevent receptor interacting protein kinase (RIPK)-dependent necrosis. Without caspase-8, mice die during embryonic development, but why this happens is not clear. Two groups show that this lethality is not caused by the absence of apoptosis, but by the RIPK3-dependent necrosis that is unleashed without caspase-8. Mice lacking both caspase-8 and RIP3 develop into viable, immunocompetent adults, but have a progressive lymphoaccumulative disease similar to that in mice that lack the CD95 death receptor. Oberst et al. also show that caspase-8 forms a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL), and that this complex is required for protection against RIP3-dependent necrosis. Caspase-8 mediates apoptosis induced by death receptors. At the same time, this protease is able to prevent RIP-dependent necrosis. Without caspase-8 mice die during their embryonic development. Two papers now show that lethality is not caused by the absence of apoptosis, but by RIP3-dependent necrosis that is unleashed without caspase-8. Mice that lack both caspase-8 and RIP3 develop into viable, immunocompetent, fertile adult mice, but suffer from a progressive lymphoaccumulative disease similar to mice that lack the death receptor CD95. This paper further shows that caspase-8 forms a proteolytically active complex with FLIPL, and that this complex is required for protection against RIP3-dependent necrosis. Caspase-8 has two opposing biological functions—it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development1, T-lymphocyte activation2, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands3,4. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL, also known as CFLAR), and this complex is required for the protective function.
1,061 citations