Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β

Luksch, Hella; Romanowski, M.J.; Chara, Osvaldo; Tüngler, Victoria; Caffarena, Ernesto R.; Heymann, Michael C.; Lohse, Peter; Aksentijevich, Ivona; Remmers, Elaine F.; Flecks, Silvana; Quoos, N; Gramatté, Johannes; Petzold, Cathleen; Hofmann, Sigrun R.; Winkler, Stefan; Peßler, Frank; Kallinich, Tilmann; Ganser, Gerd; Nimtz-Talaska, A.; Baumann, Ulrich; Runde, Volker; Grimbacher, Bodo; Birmelin, Jennifer; Gahr, Manfred; Roesler, Joachim; Rösen‐Wolff, Angela

doi:10.1002/humu.22169

Cited by 30 publications

(37 citation statements)

References 44 publications

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“…Our patients are either heterozygous or exhibit at least residual enzymatic (pro)caspase-1 activity (11). If the transfection model really applies to these patients, the remaining enzymatic activity could diminish the proinflammatory effect of the less active or inactive procaspase-1 variants by limiting protein interactions and hence limiting NF-kB activation.…”

Section: Discussionmentioning

confidence: 99%

“…Phagocytes and especially monocytes from individuals with such variants show a trend to produce decreased amounts of active IL-1b (11). Therefore, such individuals should be less prone to develop autoinflammation than others.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we characterized structure and function of different genetic variants of procaspase-1 (p.R221C, p.R240Q, p.N263S, p.L265S, p.T267I, p.K319R, and p.A329T) found in a healthy control population and in patients with recurrent febrile episodes (11). These procaspase-1 variants did not segregate with disease within families.…”

Section: Procaspase-1 Variants Are Associated With Febrile Episodesmentioning

confidence: 99%

“…Recently, we reported seven rare naturally occurring genetic variants of human procaspase-1, which exhibited altered protein structure and showed decreased or absent autoprocessing and enzymatic activity (11). However, such procaspase-1 variants with decreased activity were detected in patients with autoinflammatory disease.…”

mentioning

confidence: 99%

“…However, such procaspase-1 variants with decreased activity were detected in patients with autoinflammatory disease. Thus, we discussed possible disease modifying effects of the (pro)caspase-1 variants because they may have attenuated an otherwise more severe disorder (11). In addition, Lamkanfi et al (12) showed that procaspase-1 with a defective active center can bind receptor interacting protein kinase 2 (RIP2) and thereby activate NF-kB.…”

mentioning

confidence: 99%

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Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-κB Signaling

Heymann

Winkler

Luksch

et al. 2014

The Journal of Immunology

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The proinflammatory enzyme caspase-1 plays an important role in the innate immune system and is involved in a variety of inflammatory conditions. Rare naturally occurring human variants of the caspase-1 gene (CASP1) lead to different protein expression and structure and to decreased or absent enzymatic activity. Paradoxically, a significant number of patients with such variants suffer from febrile episodes despite decreased IL-1β production and secretion. In this study, we investigate how variant (pro)caspase-1 can possibly contribute to inflammation. In a transfection model, such variant procaspase-1 binds receptor interacting protein kinase 2 (RIP2) via Caspase activation and recruitment domain (CARD)/CARD interaction and thereby activates NF-κB, whereas wild-type procaspase-1 reduces intracellular RIP2 levels by enzymatic cleavage and release into the supernatant. We approach the protein interactions by coimmunoprecipitation and confocal microscopy and show that NF-κB activation is inhibited by anti–RIP2-short hairpin RNA and by the expression of a RIP2 CARD-only protein. In conclusion, variant procaspase-1 binds RIP2 and thereby activates NF-κB. This pathway could possibly contribute to proinflammatory signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Procaspase-1 Variants Are Associated With Febrile Episodesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-κB Signaling

Heymann

Winkler

Luksch

et al. 2014

The Journal of Immunology

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Francisella Inflammasomes: Integrated Responses to a Cytosolic Stealth Bacterium

Wallet¹,

Lagrange²,

Henry³

2016

Current Topics in Microbiology and Immunology

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Francisella tularensis is a facultative intracellular bacterium causing tularemia, a zoonotic disease. Francisella replicates in the macrophage cytosol and eventually triggers cytosolic immune responses. In murine macrophages, Francisella novicida and Francisella tularensis live vaccine strain lyse in the host cytosol and activate the cytosolic DNA receptor Aim2. Here, we review the mechanisms leading or contributing to Aim2 inflammasome activation, including the role of TLRs and of IFN signaling and the implication of the guanylate-binding proteins 2 and 5 in triggering cytosolic bacteriolysis. Furthermore, we present how this cytosolic Gram-negative bacterium escapes recognition by caspase-11 but can trigger a non-canonical caspase-8 inflammasome. In addition, we highlight the differences in inflammasome activation in murine and human cells with pyrin, NLRP3, and AIM2 involved in sensing Francisella in human phagocytes. From a bacterial prospective, we describe the hiding strategy of Francisella to escape recognition by innate sensors and to resist to bacteriolysis in the host cytosol. Finally, we discuss the inability of the inflammasome sensors to detect F. tularensis subspecies tularensis strains, making them highly pathogenic stealth microbes.

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Protective and detrimental roles of inflammasomes in disease

et al. 2015

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Over recent years, inflammasomes have emerged as key regulators of immune and inflammatory responses. They induce programmed cell death and direct the release of danger signals and the inflammatory cytokines interleukin (IL)-1β and IL-18. The concerted actions of inflammasomes are of utmost importance for responding adequately to harmful environmental agents and infections. However, deregulated inflammasome signaling is increasingly linked to a diversity of human pathologies, including rheumatoid arthritis, inflammatory bowel disease, and rare, hereditary periodic fever syndromes. In this review, we discuss recent insight in the protective and detrimental roles of inflammasomes in selected infectious, autoinflammatory and autoimmune diseases, and cover clinically approved therapies that interfere with inflammasome signaling. These findings highlight the importance of fine-balancing the Ying and Yang activities of inflammasomes for sustained homeostasis and suggest that further understanding of inflammasome mechanisms may offer new cures for human diseases.

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Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β

Cited by 30 publications

References 44 publications

Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-κB Signaling

Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-κB Signaling

Francisella Inflammasomes: Integrated Responses to a Cytosolic Stealth Bacterium

Protective and detrimental roles of inflammasomes in disease

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