Journal Article

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

Jordan, Michael B., Hildeman, David, Aksoylar, Halil I., Endale, Mehari, Kucuk, Zeynep, Woodgett, Jim R., Flagg, Aron, Singh, Harinder, Lampe, Kristin, Patterson, Andrew R., Hoebe, Kasper, Bleesing, Jack

2018

Overview

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 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 GSK3β is an important checkpoint in lymphocyte proliferation. Loss of function GIMAP5 mutation is associated with lymphopenia, but how it mediates T cell homeostasis is unclear. Here the authors study Gimap5 −/− mice and a patient with GIMAP5 deficiency to show how this GTPAse negatively regulates GSK3β activity to prevent DNA damage and cell death.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/1 / 14/19 / 14/63 / 45/23 / 631/250/2152/1566/1618 / 631/250/249/2512 / 631/250/38 / 64/110 / 64/60 / 96/31 / Animals / Autoimmunity / c-Myc protein / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - pathology / CD4-Positive T-Lymphocytes - physiology / Cell activation / Cell Death / Cell growth / Cell Proliferation / Colitis / Colitis - genetics / Colitis - immunology / Constraining / Deactivation / Deoxyribonucleic acid / DNA / DNA damage / DNA Damage - immunology / Enzyme Activation / Enzyme Inhibitors - pharmacology / Glycogen / Glycogen synthase kinase 3 / Glycogen Synthase Kinase 3 beta - antagonists & inhibitors / Glycogen Synthase Kinase 3 beta - metabolism / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / GTP-Binding Proteins - genetics / GTP-Binding Proteins - immunology / GTP-Binding Proteins - metabolism / Guanosine triphosphatases / Homeostasis / Humanities and Social Sciences / Humans / Immunity / Inactivation / Kinases / Lymphocytes / Lymphocytes T / Lymphopenia / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Myc protein / Nuclear transport / Pharmacology / Phosphorylation / Science / Science (multidisciplinary) / Translocation