Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation
- 18 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (6), 626-635
- https://doi.org/10.1038/s41590-020-0681-x
Abstract
The inflammasome NLRP6 plays a crucial role in regulating inflammation and host defense against microorganisms in the intestine. However, the molecular mechanisms by which NLRP6 function is inhibited to prevent excessive inflammation remain unclear. Here, we demonstrate that the deubiquitinase Cyld prevents excessive interleukin 18 (IL-18) production in the colonic mucosa by deubiquitinating NLRP6. We show that deubiquitination inhibited the NLRP6–ASC inflammasome complex and regulated the maturation of IL-18. Cyld deficiency in mice resulted in elevated levels of active IL-18 and severe colonic inflammation following Citrobacter rodentium infection. Further, in patients with ulcerative colitis, the concentration of active IL-18 was inversely correlated with CYLD expression. Thus, we have identified a novel regulatory mechanism that inhibits the NLRP6–IL-18 pathway in intestinal inflammation.Keywords
This publication has 46 references indexed in Scilit:
- Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasisNature Reviews Gastroenterology & Hepatology, 2018
- Inflammasomes: mechanism of assembly, regulation and signallingNature Reviews Immunology, 2016
- Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short reportCellular Oncology, 2016
- CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune SignalingCell Reports, 2016
- NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus SecretionCell, 2014
- Role of Inflammasomes in Host Defense against Citrobacter rodentium InfectionJournal of Biological Chemistry, 2012
- The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammationNature Immunology, 2011
- Commentary: The role of the IL‐18 system and other members of the IL‐1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe?European Journal of Immunology, 2004
- Transient transfection of polarized epithelial monolayers with CFTR and reporter genes using efficacious lipidsAmerican Journal of Physiology-Cell Physiology, 2003
- Bioactive IL-18 Expression Is Up-Regulated in Crohn’s DiseaseThe Journal of Immunology, 1999