title: NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.forename: John D
authors.initials: JD
authors.lastname: Lich
authors.forename: Reid A
authors.initials: RA
authors.lastname: Roberts
authors.forename: Janelle C
authors.initials: JC
authors.lastname: Arthur
authors.forename: Rita-Marie T
authors.initials: RM
authors.lastname: Woodford
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Uronis
authors.forename: Hans H
authors.initials: HH
authors.lastname: Herfarth
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C515256:Cxcl12 protein, mouse; C486386:Cxcl13 protein, mouse; C553199:NLRP12 protein, mouse