title: Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.
abstract: Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3β (GSK3β) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3β on Ser(389) by p38 MAPK (mitogen-activated protein kinase) is induced selectively by DSBs through ATM (ataxia telangiectasia mutated) as a unique mechanism to attenuate the activity of nuclear GSK3β and promote survival of cells undergoing DSBs. Inability to inactivate GSK3β through Ser(389) phosphorylation in Ser(389)Ala knockin mice causes a decrease in the fitness of cells undergoing V(D)J recombination and CSR. Preselection-Tcrβ repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3β knockin mice. Thus, GSK3β emerges as an important modulator of the adaptive immune response.
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Thornton
authors.affiliation: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 328029, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Delgado
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Salas
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Krementsov
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Fernandez
authors.affiliation: Program in Molecular Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.affiliation: Program in Molecular Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA.|Howard Hughes Medical Institute, Worcester, Massachusetts 01605, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Medicine/Radiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Heimann
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Krangel
authors.affiliation: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 328029, Spain.
authors.forename: Almudena R
authors.initials: AR
authors.lastname: Ramiro
authors.affiliation: Department of Medicine/Immunobiology, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincón
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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