2. Academic Validation
  3. Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation

Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation

  • Nat Immunol. 2020 Jun;21(6):626-635. doi: 10.1038/s41590-020-0681-x.
Sandip Mukherjee 1 2,  Ritesh Kumar 1 2,  Elviche Tsakem Lenou 1 2,  Venkatesha Basrur 3,  Dimitris L Kontoyiannis 4 5,  Fotis Ioakeimidis 5,  George Mosialos 4,  Arianne L Theiss 6,  Richard A Flavell 7,  K Venuprasad 8 9
Affiliations

Affiliations

  • 1 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
  • 2 Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 4 School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • 5 Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece.
  • 6 Division of Gastroenterology and Hepatology, School of Medicine at the Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
  • 7 Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
  • 8 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. venuprasad.poojary@utsouthwestern.edu.
  • 9 Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA. venuprasad.poojary@utsouthwestern.edu.
PMID: 32424362 DOI: 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.

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