title: Deleted in Breast Cancer 1 Suppresses B Cell Activation through RelB and Is Regulated by IKKα Phosphorylation.
abstract: Alternative NF-κB signaling is crucial for B cell activation and Ig production, and it is mainly regulated by the inhibitor of κ B kinase (IKK) regulatory complex. Dysregulation of alternative NF-κB signaling in B cells could therefore lead to hyperactive B cells and Ig overproduction. In our previous, study we found that deleted in breast cancer 1 (DBC1) is a suppressor of the alternative NF-κB pathway to attenuate B cell activation. In this study, we report that loss of DBC1 results in spontaneous overproduction of Ig in mice after 10 mo of age. Using a double mutant genetic model, we confirm that DBC1 suppresses B cell activation through RelB inhibition. At the molecular level, we show that DBC1 interacts with alternative NF-κB members RelB and p52 through its leucine zipper domain. In addition, phosphorylation of DBC1 at its C terminus by IKKα facilitates its interaction with RelB and IKKα, indicating that DBC1-mediated suppression of alternative NF-κB is regulated by IKKα. Our results define the molecular mechanism of DBC1 inhibition of alternative NF-κB activation in suppressing B cell activation.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago IL 60611;
authors.forename: Sinyi
authors.initials: S
authors.lastname: Kong
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611;
authors.forename: Hongxin
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine Chicago, Chicago, IL 60612;
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thiruppathi
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine Chicago, Chicago, IL 60612;
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago IL 60611;
authors.forename: Quan
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago IL 60611;
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Laboratory of Signal Transduction, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905; Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Chini
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago IL 60611; fangd@northwestern.edu.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000595916:KIAA1967 protein, mouse; C497593:RELB protein, human; D051841:Transcription Factor RelB; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase