title: A pathway switch directs BAFF signaling to distinct NFκB transcription factors in maturing and proliferating B cells.
abstract: BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Almaden
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Tsui
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Yi C
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Birnbaum
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Shokhirev
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Ngo
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Davis-Turak
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Otero
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Basak
authors.affiliation: Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90025, USA. Electronic address: ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053264:B-Cell Activating Factor; D020672:I-kappa B Proteins; D016328:NF-kappa B; D021122:Protein Subunits; C505720:Tnfsf13b protein, mouse