Inactivation of nuclear GSK3β by Ser(389) 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.
Duke Scholars
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Related Subject Headings
- Phosphorylation
- Mutation
- Mice
- Lymphocytes
- Humans
- Glycogen Synthase Kinase 3 beta
- Glycogen Synthase Kinase 3
- Gene Knock-In Techniques
- Gene Expression Regulation, Enzymologic
- DNA Repair
Citation
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Phosphorylation
- Mutation
- Mice
- Lymphocytes
- Humans
- Glycogen Synthase Kinase 3 beta
- Glycogen Synthase Kinase 3
- Gene Knock-In Techniques
- Gene Expression Regulation, Enzymologic
- DNA Repair