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

Andrew R. Patterson, et al.

Nature communications. 2018;9:430

Speaker: Yun-Erh Chuang (莊筠兒)               Time: 14:10~15:00, May 16, 2018                     

Commentator: Dr. Nan-Shan Chang (張南山老師)    Place: Room 601                                          

Abstract

GTPase of immunity-associated protein 5 (Gimap5) is mainly expressed in lymphocytes and is crucial for lymphocyte survival,  development, selection and homeostasis. Mice with a Gimap5 loss-of-function mutation are associated with reduction of lymphocytes and loss of immunological tolerance¹. However, the mechanisms of Gimap5 deficiency in CD4⁺ T cell are poorly understood. Glycogen synthase kinases-3 (GSK3) is a serine/threonine protein kinase, regulating various protein (c-Myc, NFATc1, Mcl-1 and β-catenin) activities such as protein ubiquitination and degradation. Previous studies have shown that GSK3β activity is inhibited when T cell is activated by antigen, thereby facilitating T cell activation and proliferation². In order to investigate the molecule that mediate a decreased proliferation of peripheral CD4⁺ T cell in Gimap5^sph/sph mice, the authors explored the activation of proximal signaling pathway in CD4⁺ T cell. They found that the protein levels of two transcription factors that are linked with GSK3β activation were either impaired or reduced, transcription factor c-Myc had a marked reduction and the nuclear translocation of NFATc1 was significantly impaired in activated Gimap5^sph/sph CD4⁺ T cell. Furthermore, it was observed that the activation of GSK3β also lead to a significant increase in DNA damage. Therefore, they explored the mechanism of how the inactivation of GSK3β in Gimap5^sph/sph CD4⁺ T cell was impaired. The results indicated that Gimap5 controls the regulation of GSK3β in activated CD4⁺ T cell through vesicular sequestration. Moreover, the GSK3β inhibitors and the genetic ablation of CD4⁺ T cell are sufficient to prevent loss of CD4⁺ T cell and immumopathology. In conclusion, Gimap5-deficient CD4⁺ T cells fail to inhibit the activation of GSK3β, thus leading to a failed transcriptional program and increased DNA damage during T cells proliferation.

Reference

1. Loss of immunological tolerance in Gimap5-deficient mice is associated with loss of Foxo in CD4⁺ T cells. J Immunol 118(1), 146-154 (2012).

2.Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3. J Immunol 190(10), 5000-5011 (2013).