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.

Caspase-1 Engagement and TLR-Induced c-FLIP Expression Suppress ASC/Caspase-8-Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4

“…In addition to its enzymatic functions as a protease, caspase-1 might exert non-enzymatic scaffolding functions, as highlighted by the identification of autoinflammatory disease patients expressing caspase-1 variants with reduced or absent catalytic activity ( Luksch et al., 2013 , Luksch et al., 2015 ). We generated knockin mice that homozygously express an enzymatically inactive caspase-1 C284A mutant from the endogenous casp1 locus to distinguish between caspase-1 enzymatic activity and caspase-1 scaffolding as mechanisms that suppress ASC- and caspase-8-dependent apoptosis ( Figures S4 A and S4B).…”

Caspases in Cell Death, Inflammation, and Disease

“…Strikingly, patients with inactivating SNPs in human CASP1 also presented with autoinflammatory disease. While the genetic variants tempered or blocked caspase-1 protease activity and IL-1b secretion, the patients present with severe inflammation, which has been proposed to be a consequence of a more robust interaction between catalytically inactive caspase-1 and the NF-kB-activating kinase RIPK2 (Kersse et al, 2011;Lamkanfi et al, 2004;Luksch et al, 2013;Luksch et al, 2015). Deficiency in IL-1Ra (DIRA) leads to uncontrolled IL-1 signaling, which-when left unattended-can be life-threatening due to development of systemic inflammation and multiorgan failure (Aksentijevich et al, 2009).…”

Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division

“…Recently, naturally occurring genetic variants of the CASP1 gene were associated with recurrent fevers and systemic inflammation in individuals with "interleukin 1-converting enzyme fever" (12,13). Caspase-1 variants exhibit reduced or absent enzymatic activity, resulting in impaired autoprocessing of inactive procaspase-1 and, subsequently, reduced cleavage, activation, and release of the pro-inflammatory cytokine IL-1␤.…”