Program in Molecular Medicine; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Immunity | Molecular Biology
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
Nat Commun. 2016 Jan 29;7:10553. doi: 10.1038/ncomms10553. Link to article on publisher's site
Thornton TM, Delgado P, Chen L, Salas B, Krementsov D, Fernandez M, Vernia S, Davis RJ, Heimann R, Teuscher C, Krangel MS, Ramiro AR, Rincon M. (2016). Inactivation of nuclear GSK3beta by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response. Davis Lab Publications. https://doi.org/10.1038/ncomms10553. Retrieved from https://escholarship.umassmed.edu/davis/17
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