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- W4313359498 abstract "Abstract GTPase of immunity-associated protein 5 (Gimap5) has been linked with lymphocyte survival, autoimmunity and colitis, but its mechanisms of action are unclear. Here we show that Gimap5 is essential for inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction as well as NFATc1 nuclear import, thereby reducing the frequency of CD4+ T cells that complete cell cycle. Additionally, Gimap5 facilitates phosphorylation of GSK3β at Ser389 and its nuclear translocation. Impairment in the latter steps of GSK3β regulation by Gimap5 is associated with increased DNA damage and reduced survival of activated CD4+ T cells. Importantly, pharmacological targeting and genetic deletion of GSK3β in mice can override Gimap5-deficiency in CD4+ T cells, limiting DNA damage and enhancing T cell proliferation and survival. Additionally, this ameliorates immune-mediated pathology in vivo caused by loss of Gimap5. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation. T cells from this patient exhibit impaired proliferation, but can be rescued in vitro with GSK3 inhibitors. Given the restricted expression of Gimap5 in lymphocytes, we propose that its control of GSK3b activity is an important checkpoint in lymphocyte proliferation and function." @default.
- W4313359498 created "2023-01-06" @default.
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- W4313359498 date "2018-05-01" @default.
- W4313359498 modified "2023-09-27" @default.
- W4313359498 title "Gimap5-dependent inactivation of GSK3β is required for CD4+ T cell homeostasis and prevention of immune pathology" @default.
- W4313359498 doi "https://doi.org/10.4049/jimmunol.200.supp.116.3" @default.
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