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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.
AuthorsHella Luksch, Stefan Winkler, Michael C Heymann, Felix Schulze, Sigrun R Hofmann, Joachim Roesler, Angela Rösen-Wolff
JournalCurrent rheumatology reports (Curr Rheumatol Rep) Vol. 17 Issue 7 Pg. 45 (Jul 2015) ISSN: 1534-6307 [Electronic] United States
PMID26003867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Caspase 1
Topics
  • Autoimmune Diseases (genetics, metabolism)
  • Caspase 1 (genetics, metabolism)
  • Fever (genetics, metabolism)
  • Genetic Variation
  • Humans
  • Immunity, Innate
  • Inflammation (genetics, metabolism)
  • Recurrence

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