2024-03-28T12:13:08Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/52522022-10-14T13:01:45Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
00925njm 22002777a 4500
dc
Thornton, Tina M.
author
Delgado, Pilar
author
Chen, Liang
author
Salas, Beatriz
author
Krementsov, Dimitry
author
Fernandez, Miriam
author
Vernia, Santiago
author
Davis, Roger J.
author
Heimann, Ruth
author
Teuscher, Cory
author
Krangel, Michael S.
author
Ramiro, Almudena R
author
Rincon, Mercedes
author
2016
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 3 beta (GSK3 beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3 beta 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 GSK3 beta and promote survival of cells undergoing DSBs. Inability to inactivate GSK3 beta 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-Tcrb repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3 beta knockin mice. Thus, GSK3 beta emerges as an important modulator of the adaptive immune response.
Nat Commun. 2016; 7:10553
2041-1723
http://hdl.handle.net/20.500.12105/5252
26822034
10.1038/ncomms10553
Nature Communications
GLYCOGEN-SYNTHASE KINASE-3-BETA
CLASS SWITCH RECOMBINATION
T-CELL DEVELOPMENT
V(D)J RECOMBINATION
DAMAGE RESPONSE
HISTONE H2AX
P38 MAPK
KINASE
MCL-1
DEATH
Inactivation of nuclear GSK3 beta by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response