Key Points
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Caspases are intracellular proteases that are divided into two subfamilies depending on whether they activate inflammation or apoptotic programmed cell death. However apoptotic caspases, particularly caspase-8 have recently been implicated in other immune processes and even cell survival.
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Mice deficient in FAS-associated via death domain (FADD), cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) or caspase-8 have a similar embryonic lethal phenotype that is not clearly related to their function in apoptosis.
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Caspase-8 also promotes differentiation of early haematopoietic precursors and monocytes.
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In mature lymphocytes, it seems that FADD promotes cell division, whereas caspase-8 promotes post-activation cell survival. Conversely, inhibition of caspase-8 expression can predispose cells to die by non-apoptotic mechanisms.
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A biochemical link between caspase-8 activation during immune-cell activation and a protein complex that activates nuclear factor-κB has been proposed.
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Viral proteins that inhibit caspases might limit antiviral immune responses in addition to blocking virus-induced cell death.
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Caspase inhibitors might modulate immune function in new ways, as well as blocking caspase-dependent cell death.
Abstract
Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death.
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Acknowledgements
I would like to thank A. Bhandoola, Y.-W. He, M. Lenardo, N. Bidére, M. Lopes, C. Walsh, and J. Zhang for helpful discussions and sharing unpublished data; J. Muppidi for assistance with the figures, and members of my laboratory for critical review of the manuscript. This work was supported by the Intramural Research Program, NIAMS, National Institutes of Health.
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Glossary
- Restimulation-induced cell death
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(RICD). Cell death that occurrs after restimulation of activated lymphocytes through the antigen receptor. Use of RICD avoids using the confusing term activation-induced cell death, which has been used to refer to cell death occurring after primary activation as well as restimulation.
- Autoimmune lymphoproliferative syndrome
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A rare childhood disease that is characterized by lymphadenopathy, splenomegaly and autoimmunity, and that is associated with heterozygous CD95 mutations in 80% of cases. This disease is also known as Canale–Smith syndrome.
- Dominant-negative protein
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A defective variant of a protein that retains the ability to interact with other proteins but lacks enzymatic activity. A dominant-negative protein thereby distorts or competes with normal variants of the protein.
- Negative selection
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The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self-peptide bound to self-MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.
- Hypogammaglobulinaemia
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A condition marked by low levels of serum immunoglobulins that occurs in patients with many different primary immunodeficiencies.
- Lymphopaenic host
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A recipient mouse that is depleted of lymphocytes. This can be done experimentally by γ-irradiation or genetic ablation of either recombination-activating gene 1 (RAG1) or RAG2. Other lymphopaenic mice include severe combined immunodeficient mice, which lack all lymphocytes, and nude mice, which lack a thymus and therefore, T cells.
- Ovalbumin-induced asthma model
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An experimental model of human allergic asthma in which mice are first sensitized to, then challenged with, ovalbumin. This leads to airway hyper-reactivity, a cardinal feature of asthma in humans.
- p21
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p21 (also known as WAF1, CIP1 and CDKN1A) is a cell-cycle inhibitor that binds to and inhibits the activity of cyclin–CDK2 (cyclin-dependent kinase 2) and cyclin–CDK4 complexes, thereby functioning as a regulator of cell-cycle progression at the G1 phase of the cell cycle.
- Lipid rafts
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Specialized membrane domains that are enriched in cholesterol and glycosphingolipids, and proteins that function in signal transduction. Rafts are often equated with 'detergent-resistant membranes', which can be isolated by density-gradient centrifugation as a function of their high buoyancy.
- K63-linked ubiquitylation
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The addition of ubiquitin to lysine side chains of target proteins using the lysine at position 63 (K63) in ubiquitin. K63-linked ubiquitin-modified proteins function in DNA repair, the stress response, mitochondrial DNA inheritance and the targeting of certain proteins for endocytosis, unlike K48-linked chains which are the principal signal for targeting substrates for proteasomal degradation.
- Jurkat T cell
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A human leukaemic T-cell line used to study several aspects of T-cell biology and signalling, in particular, signal-transduction events initiated by the T-cell receptor.
- Immunoprecipitated
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Proteins that have been purified by binding to specific antibodies immobilized to a solid-phase support.
- Small interfering RNA
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(siRNA). Short (∼21-base pairs) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.
- Autophagic-cell morphology
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The electron microscopic appearance of cells marked by expanded double-walled phagocytic vesicles that are termed autophagosomes.
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Siegel, R. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6, 308–317 (2006). https://doi.org/10.1038/nri1809
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DOI: https://doi.org/10.1038/nri1809
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