Gsk3 is a metabolic checkpoint regulator in B cells

• DOI: 10.1038/ni.3664
• Publication Date: 2017-01-23T20:27:03Z
• Authors: Julia Jellusova; Matthew H Cato; John R Apgar; Parham Ramezani-Rad; Charlotte R Leung; Cindi Chen; Adam D Richardson; Elaine M Conner; Robert J Benschop; James R Woodgett; Robert C Rickert
• Keywords: Mice, Knockout; B-Lymphocytes; 0303 health sciences; Glycogen Synthase Kinase 3 beta; Antigens, CD19; CD40 Ligand; Apoptosis; Cell Differentiation; Germinal Center; Article; Mice; Oxidative Stress; 03 medical and health sciences; Animals; Interleukin-4; Reactive Oxygen Species; Glycolysis; Cells, Cultured; Cell Proliferation; Signal Transduction

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.