title: Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways.
abstract: The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses.
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Vincent F-S
authors.initials: VF
authors.lastname: Shih
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis-Turak
authors.forename: Monica
authors.initials: M
authors.lastname: Macal
authors.forename: Jenny Q
authors.initials: JQ
authors.lastname: Huang
authors.forename: Julia
authors.initials: J
authors.lastname: Ponomarenko
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearns
authors.forename: Tony
authors.initials: T
authors.lastname: Yu
authors.forename: Riku
authors.initials: R
authors.lastname: Fagerlund
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.forename: Elina I
authors.initials: EI
authors.lastname: Zuniga
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C497594:Relb protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051841:Transcription Factor RelB; D051550:I-kappa B Kinase