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

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. Double stranded DNA breaks are generated during rearrangements of lymphocyte antigen receptors. Here the authors show that the DNA breaks induce phosphorylation of nuclear GSK3β at Ser 389 /Thr 390 , protecting the activated lymphocytes from necroptosis-mediated cell death.