Deubiquitination of NLRP6 by Cyld critically regulates colonic inflammation

Abstract The inflammasome NLRP6 plays a crucial role in regulating colonic inflammation and cancer. 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 and increased colon cancer. 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 colonic inflammation. (Nat Immunol. 2020. 21(6):626–635. PMID: 32424362)