Open AccessDeubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation
Author(s) -
Sandip Mukherjee,
Ritesh Kumar,
Elviche Tsakem Lenou,
Venkatesha Basrur,
Dimitris L. Kontoyiannis,
Fotis Ioakeimidis,
George Mosialos,
Arianne L. Theiss,
Richard A. Flavell,
K. Venuprasad
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0681-x
Subject(s) - inflammasome , deubiquitinating enzyme , inflammation , interleukin 18 , ubiquitin , intestinal mucosa , biology , immunology , cancer research , chemistry , microbiology and biotechnology , cytokine , medicine , biochemistry , gene
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.