Gimap5-dependent inactivation of GSK3β is required for CD4⁺ T cell homeostasis and prevention of immune pathology.

ABSTRACT: GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4⁺ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3β, thereby limiting DNA damage in CD4⁺ T cells. Importantly, pharmacological inhibition and genetic targeting of GSK3β can override Gimap5 deficiency in CD4⁺ T cells and ameliorates immunopathology in mice. Finally, we show that a hu

SUBMITTER: Patterson AR 

PROVIDER: S-EPMC5789891 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature