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

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
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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.

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Acknowledgments

S.W., J.R., S.H., and A.RW. were supported by the Deutsche Forschungsgemeinschaft (WI 4269/1-2, HO 4510/1-1 and 2, RO 847/11-1 and 2) and by the Federal Ministry of Education and Research (BMBF) in PID-NET TPA4 (01GM1111C).

The p.A68P/WT variant was detected by Raphaela Goldbach-Mansky (NIH) and left to the authors for functional analyses.

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The authors declare that they have no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 03107, Dresden, Germany

    Hella Luksch, Stefan Winkler, Michael C. Heymann, Felix Schulze, Sigrun R. Hofmann, Joachim Roesler & Angela Rösen-Wolff

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  1. Hella Luksch
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Correspondence to Angela Rösen-Wolff.

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Luksch, H., Winkler, S., Heymann, M.C. et al. Current Knowledge on Procaspase-1 Variants with Reduced or Abrogated Enzymatic Activity in Autoinflammatory Disease. Curr Rheumatol Rep 17, 45 (2015). https://doi.org/10.1007/s11926-015-0520-5

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