Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation

Sandip Mukherjee, Ritesh Kumar, Elviche Tsakem Lenou, Venkatesha Basrur, Dimitris L. Kontoyiannis, Fotis Ioakeimidis, George Mosialos, Arianne L. Theiss, Richard A. Flavell, K. Venuprasad

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)626-635
Number of pages10
JournalNature immunology
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Mukherjee, S., Kumar, R., Tsakem Lenou, E., Basrur, V., Kontoyiannis, D. L., Ioakeimidis, F., Mosialos, G., Theiss, A. L., Flavell, R. A., & Venuprasad, K. (2020). Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation. Nature immunology, 21(6), 626-635. https://doi.org/10.1038/s41590-020-0681-x