GIMAP6 is required for T cell maintenance and efficient autophagy in mice

Abstract

The GTPases of the immunity-associated proteins (GIMAP) GTPases are a family of proteins expressed strongly in the adaptive immune system. We have previously reported that in human cells one member of this family, GIMAP6, interacts with the ATG8 family member GABARAPL2, and is recruited to autophagosomes upon starvation, suggesting a role for GIMAP6 in the autophagic process. To study this possibility and the function of GIMAP6 in the immune system, we have established a mouse line in which the Gimap6 gene can be inactivated by Cre-mediated recombination. In mice bred to carry the CD2Cre transgene such that the Gimap6 gene was deleted within the T and B cell lineages there was a 50–70% reduction in peripheral CD4+ and CD8+ T cells. Analysis of splenocyte-derived proteins from these mice indicated increased levels of MAP1LC3B, particularly the lipidated LC3-II form, and S405-phosphorylation of SQSTM1. Electron microscopic measurements of Gimap6-/- CD4+ T cells indicated an increased mitochondrial/cytoplasmic volume ratio and increased numbers of autophagosomes. These results are consistent with autophagic disruption in the cells. However, Gimap6-/- T cells were largely normal in character, could be effectively activated in vitro and supported T cell-dependent antibody production. Treatment in vitro of CD4+ splenocytes from GIMAP6fl/flERT2Cre mice with 4-hydroxytamoxifen resulted in the disappearance of GIMAP6 within five days. In parallel, increased phosphorylation of SQSTM1 and TBK1 was observed. These results indicate a requirement for GIMAP6 in the maintenance of a normal peripheral adaptive immune system and a significant role for the protein in normal autophagic processes. Moreover, as GIMAP6 is expressed in a cell-selective manner, this indicates the potential existence of a cell-restricted mode of autophagic regulation.

Transcriptomic study in women with trisomy 21 identifies a possible role of the GTPases of the immunity-associated proteins (GIMAP) in the protection of breast cancer

“…In fact, in addition to their involvement in the regulation of the immune system, GIMAPs might act as tumor suppressor genes, as was speculated by Krucken et al who showed that all GIMAPs are expressed at very low levels in diverse cancer tissues and cell lines 22 . This hypothesis was further confirmed by other studies that proved that GIMAP4 accelerates the execution of programmed cell death 15 , while GIMAP6 plays a role in the autophagic process 23 . On the other hand, a study on non-small cell lung cancer (NSCLC) showed that the expression of GIMAP4, GIMAP6, and GIMAP8 were lower in tumor tissues than in adjacent non-tumor tissues 24 .…”

A human case of GIMAP6 deficiency: a novel primary immune deficiency

“…It also lead to more rapid T cell activation following stimulation by PMA and ionomycin, and the authors showed for the first time that GIMAP6 can function as an ATPase (the only member of the GIMAP family shown to do so) [8]. In 2018, Pascall et al [15,16] established a knockout mouse model of GIMAP6 deficiency and showed that these mice suffered a 50-70% reduction in the numbers of circulating CD4+ and CD8+ lymphocytes as well as reduced autophagy.…”

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

“…GIMAPs are involved in the development, maintenance, and homeostasis of lymphocytes, especially CD4 + T cells and B cells, but also T regulatory cells (Tregs) (53)(54)(55). In the absence of individual GIMAP members, there is progressive lymphocyte loss leading to lymphopenia, poor cell proliferation, and paradoxical autoimmune states because of impaired Treg function (54)(55)(56)(57)(58). A previous gene family analysis showed that the GIMAP family is expanded in the Egyptian rousette compared to a bat ancestor (19), with 14 putative members.…”