Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation

• Published in: Nature immunology Vol. 21; no. 6; pp. 626 - 635
• Main Authors: Mukherjee, Sandip, Kumar, Ritesh, Tsakem Lenou, Elviche, Basrur, Venkatesha, Kontoyiannis, Dimitris L., Ioakeimidis, Fotis, Mosialos, George, Theiss, Arianne L., Flavell, Richard A., Venuprasad, K.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Nature Publishing Group
• Subjects: 631/250; 692/699; 706/648; Animals; Biomedical and Life Sciences; Biomedicine; Citrobacter rodentium; Deubiquitinating Enzyme CYLD - genetics; Deubiquitinating Enzyme CYLD - metabolism; Disease Models, Animal; Disease Susceptibility; Enterobacteriaceae Infections - immunology; Enterobacteriaceae Infections - metabolism; Enterobacteriaceae Infections - microbiology; Enterobacteriaceae Infections - pathology; Enterocolitis - etiology; Enterocolitis - metabolism; Enterocolitis - pathology; Gene Expression; Health aspects; Humans; Immunology; Infection; Infectious Diseases; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interleukin 18; Interleukin-18 - antagonists & inhibitors; Interleukin-18 - metabolism; Interleukins; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Mice; Mice, Knockout; Microorganisms; Molecular modelling; Mucosa; Protein Binding - immunology; Receptors, Cell Surface - metabolism; Scientific equipment and supplies industry; Ubiquitin; Ubiquitination; Ulcerative colitis; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-0681-x

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. NLRP6 is highly expressed in the gut; however, persistent NLRP6 activation can lead to excessive IL-18 production and intestinal bowel disease. Venuprasad and colleagues identify the K63-linked ubiquitin deubiquitinase Cyld as a negative regulator of NLRP6.