title: Current knowledge on procaspase-1 variants with reduced or abrogated enzymatic activity in autoinflammatory disease.
abstract: Caspase-1 is a proinflammatory enzyme that is essential in many inflammatory conditions including infectious, autoimmune, and autoinflammatory disorders. The inflammation is mainly mediated by the generation of inflammasomes that activate caspase-1 and subsequently interleukin (IL)-1β and IL-18. In addition, homotypic CARD/CARD interaction of procaspase-1 with RIP2 and thereby activation of the NF-κB pathways may play some role in the inflammation. However, normally, this pathway seems to become downregulated rapidly by the cleavage and excretion of RIP2 by active (pro-)caspase-1. In patients with unexplained recurrent systemic inflammation, CASP1 variants were detected, which often destabilized the caspase-1 dimer interface. Obviously, the resulting decreased or abrogated enzymatic activity and IL-1β production did not prevent the febrile episodes. As an unexpected finding, the inactive procaspase-1 variants significantly enhanced proinflammatory signaling by increasing RIP2 mediated NF-κB activation in an in vitro cell transfection model. A likely reason is the failure of inactive procaspase-1 to cleave bound RIP2 and also to mediate its excretion out of the intracelluar space thereby keeping the RIP2-NF-κB pathway upregulated. Hence, proinflammatory effects of enzymatically inactive procaspase-1 variants may partially explain the inflammatory episodes of the patients.
authors.affiliation: Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 03107, Dresden, Germany, Hella.Luksch@uniklinikum-dresden.de.
authors.forename: Hella
authors.initials: H
authors.lastname: Luksch
authors.forename: Stefan
authors.initials: S
authors.lastname: Winkler
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heymann
authors.forename: Felix
authors.initials: F
authors.lastname: Schulze
authors.forename: Sigrun R
authors.initials: SR
authors.lastname: Hofmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Angela
authors.initials: A
authors.lastname: Rösen-Wolff
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D005334:Fever / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence
chemical_list: D020170:Caspase 1