NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling

Irving C. Allen, Justin E. Wilson, Monika Schneider, John D. Lich, Reid A. Roberts, Janelle C. Arthur, Rita Marie T. Woodford, Beckley K. Davis, Joshua M. Uronis, Hans H. Herfarth, Christian Jobin, Arlin B. Rogers, Jenny P.Y. Ting

Research output: Contribution to journalArticlepeer-review

339 Scopus citations

Abstract

In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-κB, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB 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-κB 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-κB 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-κB, inflammation, and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)742-754
Number of pages13
JournalImmunity
Volume36
Issue number5
DOIs
StatePublished - May 25 2012
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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