Abstract
Caspase-1 is a unique cysteine protease playing central roles in innate immunity. Pathogens, stress, and damage signals induce activation of caspase-1, typically mediated by proximity-induced autoproteolysis in multimeric protein complexes called the inflammasome. Active caspase-1 induces secretion of pro-inflammatory cytokines and mediates pyroptosis, a programmed pro-inflammatory cell death, thereby initiating an immune response finally leading to pathogen clearance. Excessive activation of caspase-1 is the underlying cause for rare diseases such as periodic fever syndromes, and more common disorders, including atherosclerosis, type 2 diabetes, and gout. Beside these well-known pro-inflammatory functions, active caspase-1 also has anti-inflammatory and protective functions contributing to cell survival, reduced inflammatory cytokine signaling, and improved outcomes in mouse models of burn injury or trauma and shock. Furthermore, naturally occurring procaspase-1 variants with reduced or abrogated enzymatic activity mediate enhanced inflammatory signaling and have been associated to autoinflammatory symptoms. Here, we review functions of caspase-1 focusing on anti-inflammatory signaling pathways and discuss the role of enzymatically inactive caspase-1 as disease-promoting factors in autoinflammatory diseases. Moreover, we illustrate differential requirements for autoproteolysis and enzymatic activity in caspase-1 functions.
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We thank Christian Hedrich and Jochen Roesler for fruitful discussions and critical reading of the manuscript.
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This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases - Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen
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Winkler, S., Rösen-Wolff, A. Caspase-1: an integral regulator of innate immunity. Semin Immunopathol 37, 419–427 (2015). https://doi.org/10.1007/s00281-015-0494-4
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DOI: https://doi.org/10.1007/s00281-015-0494-4