| First Author | Thornton TM | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 10553 | PubMed ID | 26822034 |
| Mgi Jnum | J:236293 | Mgi Id | MGI:5805631 |
| Doi | 10.1038/ncomms10553 | Citation | Thornton TM, et al. (2016) Inactivation of nuclear GSK3beta by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response. Nat Commun 7:10553 |
| abstractText | 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 3beta (GSK3beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3beta 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 GSK3beta and promote survival of cells undergoing DSBs. Inability to inactivate GSK3beta 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-Tcrbeta repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3beta knockin mice. Thus, GSK3beta emerges as an important modulator of the adaptive immune response. |
