Current Knowledge on Procaspase-1 Variants with Reduced or Abrogated Enzymatic Activity in Autoinflammatory Disease

• Published in: Current rheumatology reports 2015-07, Vol.17 (7), p.45-45, Article 45
• Main Authors: Luksch, Hella, Winkler, Stefan, Heymann, Michael C., Schulze, Felix, Hofmann, Sigrun R., Roesler, Joachim, Rösen-Wolff, Angela
• Format: Article
• Language: English
• Subjects: Autoimmune Diseases - genetics; Autoimmune Diseases - metabolism; Caspase 1 - genetics; Caspase 1 - metabolism; Fever - genetics; Fever - metabolism; Genetic Variation; Humans; Immunity, Innate; Inflammation - genetics; Inflammation - metabolism; Medicine; Medicine & Public Health; Pediatric Rheumatology (S Ozen; Recurrence; Rheumatology; Section Editor; Topical Collection on Pediatric Rheumatology
• ISSN: 1523-3774; 1534-6307
• DOI: 10.1007/s11926-015-0520-5

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.