title: FOXO3-NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function.
abstract: Tumor-associated myeloid cells, including dendritic cells (DCs) and macrophages, are immune suppressive. This study demonstrates a novel mechanism involving FOXO3 and NF-κB RelA that controls myeloid cell signaling and impacts their immune-suppressive nature. We find that FOXO3 binds NF-κB RelA in the cytosol, impacting both proteins by preventing FOXO3 degradation and preventing NF-κB RelA nuclear translocation. The location of protein-protein interaction was determined to be near the FOXO3 transactivation domain. In turn, NF-κB RelA activation was restored upon deletion of the same sequence in FOXO3 containing the DNA binding domain. We have identified for the first time, to our knowledge, a direct protein-protein interaction between FOXO3 and NF-κB RelA in tumor-associated DCs. These detailed biochemical interactions provide the foundation for future studies to use the FOXO3-NF-κB RelA interaction as a target to enhance tumor-associated DC function to support or enhance antitumor immunity.
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Thompson
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Larson
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Amy
authors.initials: A
authors.lastname: Vidrine
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Kelly
authors.identifier: http://orcid.org/0000-0001-9694-0563
authors.initials: K
authors.lastname: Barrios
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Flor
authors.initials: F
authors.lastname: Navarro
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Meyers
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Patricia
authors.identifier: http://orcid.org/0000-0002-7257-9627
authors.initials: P
authors.lastname: Simms
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Kushal
authors.initials: K
authors.lastname: Prajapati
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and.
authors.forename: Lennox
authors.identifier: http://orcid.org/0000-0002-2901-353X
authors.initials: L
authors.lastname: Chitsike
authors.affiliation: Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Lance M
authors.identifier: http://orcid.org/0000-0002-4938-6296
authors.initials: LM
authors.lastname: Hellman
authors.affiliation: Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; and swatkins1@luc.edu.
authors.forename: Stephanie K
authors.identifier: http://orcid.org/0000-0002-5573-1316
authors.initials: SK
authors.lastname: Watkins
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B