Abstract
Gimap5 (GTPase of the immunity-associated protein 5) has been linked to the regulation of T cell survival, and polymorphisms in the human GIMAP5 gene associate with autoimmune disorders. The BioBreeding diabetes-prone (BBDP) rat has a mutation in the Gimap5 gene that leads to spontaneous apoptosis of peripheral T cells by an unknown mechanism. Because Gimap5 localizes to the endoplasmic reticulum (ER), we hypothesized that absence of functional Gimap5 protein initiates T cell death through disruptions in ER homeostasis. We observed increases in ER stress-associated chaperones in T cells but not thymocytes or B cells from Gimap5−/− BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap5−/− T cells. Knockdown of CHOP by siRNA protected Gimap5−/− T cells from ER stress-induced apoptosis, thereby identifying a role for this cellular pathway in the T cell lymphopenia of the BBDP rat. These findings indicate a direct relationship between Gimap5 and the maintenance of ER homeostasis in the survival of T cells.
Highlights
The expression products of the GTPase of the immunityassociated gene family have been implicated in the regulation of T cell survival through modulation of T cell receptor (TCR) signaling [1,2]
To examine the potential role of endoplasmic reticulum (ER) stress in T cell death of Gimap52/2 rats, we compared the expression of ER chaperone proteins in lymph node cells and thymocyte lysates from Gimap52/2 BioBreeding diabetes-prone (BBDP) and Gimap5+/+ BioBreeding diabetes-resistant (BBDR) rats
Western blot analyses revealed that GRP94, Glucose-regulated protein 78 (GRP78), and ER protein 72 (ERp72) levels were increased in lymphocytes from Gimap52/2 BBDP rats when compared to that in Gimap5+/+ BBDR rats (Fig. 1)
Summary
The expression products of the GTPase of the immunityassociated gene family (gimaps; formerly known as IANs or immune-associated nucleotide-binding proteins) have been implicated in the regulation of T cell survival through modulation of T cell receptor (TCR) signaling [1,2]. A member of this family, GIMAP5, has an important role in human immune modulation as a polyadenylation polymorphism in the human GIMAP5 gene increases systemic lupus erythematosus risk [3] and is associated with elevated islet autoantibodies in type 1 diabetics [4]. Absence of functional wild type Gimap protein results in mitochondrial dysfunction and apoptosis in vitro, and severe T cell lymphopenia in vivo [9,10,11]. The mechanism by which Gimap promotes T cell survival is not understood
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