UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network

Date

1-29-2016

Document Type

Article

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Immunity | Molecular Biology

Abstract

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.

Rights and Permissions

Citation: Nat Commun. 2016 Jan 29;7:10553. doi: 10.1038/ncomms10553. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

26822034

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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