| First Author | Patterson AR | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 430 |
| PubMed ID | 29382851 | Mgi Jnum | J:260013 |
| Mgi Id | MGI:6114864 | Doi | 10.1038/s41467-018-02897-7 |
| Citation | Patterson AR, et al. (2018) Gimap5-dependent inactivation of GSK3beta is required for CD4(+) T cell homeostasis and prevention of immune pathology. Nat Commun 9(1):430 |
| abstractText | 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-3beta (GSK3beta) following T cell activation. In the absence of Gimap5, constitutive GSK3beta 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 GSK3beta, thereby limiting DNA damage in CD4(+) T cells. Importantly, pharmacological inhibition and genetic targeting of GSK3beta can override Gimap5 deficiency in CD4(+) T cells and ameliorates immunopathology in mice. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors. Given that the expression of Gimap5 is lymphocyte-restricted, we propose that its control of GSK3beta is an important checkpoint in lymphocyte proliferation. |
