Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis

Reygaerts, T; Laohamonthonkul, P; Hrovat-Schaale, K; Moghaddas, F; Baker, PJ; Gray, PE; Masters, SL

Author(s): Reygaerts, T; Laohamonthonkul, P; Hrovat-Schaale, K; Moghaddas, F; Baker, PJ; Gray, PE; Masters, SL;
Details: Publication Year 2024-07-22,Volume 63,Issue #3,Page 882-890
Journal Title: Rheumatology
Abstract: OBJECTIVE: The p.E148Q variant in pyrin is present in different populations at a frequency up to 29%, and has been associated with diseases including vasculitis and familial Mediterranean fever (FMF). The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines. METHODS: We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC) which were analysed by flow cytometry to visualise inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors. RESULTS: In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harbored the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1beta and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation. CONCLUSION: The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease.
Publisher: Oxford Academic
Research Division(s): Inflammation; Ubiquitin Signalling; Ubiquitin Signalling
PubMed ID: 37481715
Publisher's Version: https://doi.org/10.1093/rheumatology/kead376
Open Access at Publisher's Site: https://doi.org/ 10.1093/rheumatology/kead376
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-04 12:44:15

Last Modified: 2024-03-11 10:02:37