NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-?B signaling.

ABSTRACT: In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-?B, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-?B activity is associated with colonic inflammation and cancer, and we found Nlrp12(-/-) mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12(-/-) mice showed elevated noncanonical NF-?B activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-?B pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12(-/-) cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-?B, inflammation, and tumorigenesis.

SUBMITTER: Allen IC 

PROVIDER: S-EPMC3658309 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature