Inactivation of nuclear GSK3β by Ser389 phosphorylation promotes lymphocyte fitness during DNA double-strand break response

Tina M. Thornton, Pilar Delgado, Liang Chen, Beatriz Salas, Dimitry Krementsov, Miriam Fernandez, Santiago Vernia, Roger J. Davis, Ruth Heimann, Cory Teuscher, Michael S. Krangel, Almudena R. Ramiro and Mercedes Rincón ()
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Tina M. Thornton: University of Vermont
Pilar Delgado: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Liang Chen: Duke University Medical Center
Beatriz Salas: University of Vermont
Dimitry Krementsov: University of Vermont
Miriam Fernandez: University of Vermont
Santiago Vernia: Program in Molecular Medicine, University of Massachusetts
Roger J. Davis: Program in Molecular Medicine, University of Massachusetts
Ruth Heimann: University of Vermont
Cory Teuscher: University of Vermont
Michael S. Krangel: Duke University Medical Center
Almudena R. Ramiro: B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Mercedes Rincón: University of Vermont

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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 Ser389 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 Ser389 phosphorylation in Ser389Ala 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 Ser389GSK3β knockin mice. Thus, GSK3β emerges as an important modulator of the adaptive immune response.

Date: 2016
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DOI: 10.1038/ncomms10553

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