title: Gsk3 is a metabolic checkpoint regulator in B cells.
abstract: B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40. Gsk3 was required to prevent metabolic collapse and ROS-induced apoptosis after glucose became limiting, functioning in part by repressing growth dependent on the myelocytomatosis oncoprotein c-Myc. Notably, we found that Gsk3 was required for the generation and maintenance of germinal center B cells, which require high glycolytic activity to support growth and proliferation in a hypoxic microenvironment.
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Jellusova
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Cato
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Apgar
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Parham
authors.initials: P
authors.lastname: Ramezani-Rad
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Leung
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Cindi
authors.initials: C
authors.lastname: Chen
authors.affiliation: NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Richardson
authors.affiliation: Eli Lilly and Company, La Jolla, California, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Conner
authors.affiliation: Eli Lilly and Company, La Jolla, California, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Benschop
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James R
authors.identifier: 0000-0003-3731-5797
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.|NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology*; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018941:Antigens, CD19; D017382:Reactive Oxygen Species; D023201:CD40 Ligand; D015847:Interleukin-4; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse