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Annual Review of Immunology Apr 2020Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated... (Review)
Review
Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D-induced pyroptosis.
Topics: Animals; Apoptosis; Biomarkers; Caspases; Cell Death; Disease Susceptibility; Enzyme Activation; Humans; Inflammation; Neoplasm Proteins; Pyroptosis; Signal Transduction
PubMed: 32017655
DOI: 10.1146/annurev-immunol-073119-095439 -
Immunity Jun 2019Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational... (Review)
Review
Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic, and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases and outline important topics for future experimentation.
Topics: Animals; Apoptosis; Biomarkers; Caspases; Cell Death; Cytokines; Disease Susceptibility; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Molecular Targeted Therapy; Pyroptosis; Signal Transduction
PubMed: 31216460
DOI: 10.1016/j.immuni.2019.05.020 -
Acta Biochimica Et Biophysica Sinica Nov 2005Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is... (Review)
Review
Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is regulated in an orderly way by a series of signal cascades under certain circumstances. The caspase-cascade system plays vital roles in the induction, transduction and amplification of intracellular apoptotic signals. Caspases, closely associated with apoptosis, are aspartate-specific cysteine proteases and members of the interleukin-1beta-converting enzyme family. The activation and function of caspases, involved in the delicate caspase-cascade system, are regulated by various kinds of molecules, such as the inhibitor of apoptosis protein, Bcl-2 family proteins, calpain, and Ca2+. Based on the latest research, the members of the caspase family, caspase-cascade system and caspase-regulating molecules involved in apoptosis are reviewed.
Topics: Animals; Apoptosis; Caspases; Cell Physiological Phenomena; Humans; Models, Biological; Signal Transduction
PubMed: 16270150
DOI: 10.1111/j.1745-7270.2005.00108.x -
Molecular Cell Mar 2002Caspases are central components of the machinery responsible for apoptosis. Recent structural and biochemical studies on procaspases, IAPs, Smac/DIABLO, and apoptosome... (Review)
Review
Caspases are central components of the machinery responsible for apoptosis. Recent structural and biochemical studies on procaspases, IAPs, Smac/DIABLO, and apoptosome have revealed a conserved mechanism of caspase activation and inhibition. This article reviews these latest advances and presents our current understanding of caspase regulation during apoptosis.
Topics: Animals; Apoptosis; Binding Sites; Caspase Inhibitors; Caspases; Enzyme Activation; Inhibitor of Apoptosis Proteins; Insect Proteins; Models, Biological; Models, Molecular; Protein Conformation; Protein Precursors; Protein Structure, Tertiary; Proteins
PubMed: 11931755
DOI: 10.1016/s1097-2765(02)00482-3 -
Cold Spring Harbor Perspectives in... Apr 2013Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes... (Review)
Review
Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.
Topics: Animals; Apoptosis; Caspases; Cell Death; Dimerization; Gene Expression Regulation; Humans; Immunity, Innate; Inflammation; Mice; Necrosis; Neoplasms; Signal Transduction; Toll-Like Receptors
PubMed: 23545416
DOI: 10.1101/cshperspect.a008656 -
Cold Spring Harbor Perspectives in... Dec 2015In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells. There are three major... (Review)
Review
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.
Topics: Animals; Apoptosis; Autophagy; Caspases; Cell Death; Models, Biological; Necrosis; Signal Transduction; Vertebrates
PubMed: 26626938
DOI: 10.1101/cshperspect.a006080 -
Cell Dec 2014Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo....
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.
Topics: Animals; Apoptosis; Caspase 9; Caspases; Crosses, Genetic; DNA, Mitochondrial; Female; Hematopoietic Stem Cells; Interferon Type I; Male; Membrane Proteins; Mice, Inbred C57BL; Signal Transduction
PubMed: 25525874
DOI: 10.1016/j.cell.2014.11.036 -
International Journal of Molecular... Feb 2021Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it... (Review)
Review
Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11-describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease.
Topics: Animals; Caspases; Humans; Inflammasomes; Protein Conformation; Pyroptosis
PubMed: 33546173
DOI: 10.3390/ijms22041506 -
Biochimica Et Biophysica Acta.... Jun 2020Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator... (Review)
Review
Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis. Many conventional cancer therapies induce apoptosis to remove the cancer cell by engaging these caspases indirectly. Newer therapeutic applications have been designed, including those that specifically activate individual caspases using gene therapy approaches and small molecules that repress natural inhibitors of caspases already present in the cell. For such approaches to have maximal clinical efficacy, emerging insights into non-apoptotic roles of these caspases need to be considered. This review will discuss the roles of caspases as safeguards against cancer in the context of the advantages and potential limitations of targeting apoptotic caspases for the treatment of cancer.
Topics: Antineoplastic Agents; Apoptosis; Caspases; Gene Expression Regulation, Neoplastic; Humans; Models, Molecular; Neoplasms; Signal Transduction
PubMed: 32087180
DOI: 10.1016/j.bbamcr.2020.118688 -
Frontiers in Immunology 2022In the early 2000s, caspase-1, an important molecule that has been shown to be involved in the regulation of inflammation, cell survival and diseases, was given a new... (Review)
Review
In the early 2000s, caspase-1, an important molecule that has been shown to be involved in the regulation of inflammation, cell survival and diseases, was given a new function: regulating a new mode of cell death that was later defined as pyroptosis. Since then, the inflammasome, the inflammatory caspases (caspase-4/5/11) and their substrate gasdermins (gasdermin A, B, C, D, E and DFNB59) has also been reported to be involved in the pyroptotic pathway, and this pathway is closely related to the development of various diseases. In addition, important apoptotic effectors caspase-3/8 and granzymes have also been reported to b involved in the induction of pyroptosis. In our article, we summarize findings that help define the roles of inflammasomes, inflammatory caspases, gasdermins, and other mediators of pyroptosis, and how they determine cell fate and regulate disease progression.
Topics: Caspase 3; Caspases; Granzymes; Humans; Inflammasomes; Inflammation; Pyroptosis
PubMed: 36189207
DOI: 10.3389/fimmu.2022.991044