Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

Citation data:

Nature communications, ISSN: 2041-1723, Vol: 7, Page: 10553

Publication Year:
2016
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Repository URL:
https://escholarship.umassmed.edu/davis/17
PMID:
26822034
DOI:
10.1038/ncomms10553
PMCID:
PMC4740185
Author(s):
Thornton, Tina M.; Delgado, Pilar; Chen, Liang; Salas, Beatriz; Krementsov, Dimitry; Fernandez, Miriam; Vernia, Santiago; Davis, Roger J.; Heimann, Ruth; Teuscher, Cory; Krangel, Michael S.; Ramiro, Almudena R.; Rincon, Mercedes Show More Hide
Publisher(s):
Springer Nature; Nature Research
Tags:
Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy; Biochemistry; Cell Biology; Cellular and Molecular Physiology; Immunity; Molecular Biology
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article description
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.