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oai:repisalud.isciii.es:20.500.12105/52522024-09-27T07:56:39Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Thornton, Tina M. author Delgado, Pilar author Chen, Liang author Salas, Beatriz author Krementsov, Dimitry author Fernandez, Miriam author Vernia, Santiago author Davis, Roger J. author Heimann, Ruth author Teuscher, Cory author Krangel, Michael S. author Ramiro, Almudena R author Rincon, Mercedes author 2016 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 3 beta (GSK3 beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3 beta 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 GSK3 beta and promote survival of cells undergoing DSBs. Inability to inactivate GSK3 beta 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-Tcrb repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3 beta knockin mice. Thus, GSK3 beta emerges as an important modulator of the adaptive immune response. Nat Commun. 2016; 7:10553 10.1038/ncomms10553 2041-1723 Nature Communications 26822034 http://hdl.handle.net/20.500.12105/5252 GLYCOGEN-SYNTHASE KINASE-3-BETA CLASS SWITCH RECOMBINATION T-CELL DEVELOPMENT V(D)J RECOMBINATION DAMAGE RESPONSE HISTONE H2AX P38 MAPK KINASE MCL-1 DEATH Inactivation of nuclear GSK3 beta by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response