UMMS Affiliation
Program in Molecular Medicine; UMass Metabolic Network
Publication Date
2016-01-29
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.
DOI of Published Version
10.1038/ncomms10553
Source
Nat Commun. 2016 Jan 29;7:10553. doi: 10.1038/ncomms10553. Link to article on publisher's site
Journal/Book/Conference Title
Nature communications
Related Resources
PubMed ID
26822034
Repository Citation
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.; and Rincon, Mercedes, "Inactivation of nuclear GSK3beta by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response" (2016). Davis Lab Publications. 17.
https://escholarship.umassmed.edu/davis/17
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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