Keita Mamadou, Leblanc Chantal, Andrews David, Ramanathan Sheela
Immunology Division, Department of Pediatrics, FMSS, University of Sherbrooke, 3001-12th Avenue North, Sherbrooke, Que., Canada J1H5N4.
Biochem Biophys Res Commun. 2007 Sep 21;361(2):481-6. doi: 10.1016/j.bbrc.2007.07.048. Epub 2007 Jul 23.
Spontaneous apoptosis of T lymphocytes results in marked lymphopenia in the Biobreeding diabetes-prone (BB-DP) rat leading to the development of autoimmune type 1 diabetes. The lymphopenia phenotype in these rats is linked to the lyp locus. The lyp allele harbors a frameshift mutation within the gene encoding 'GTPase of immunity-associated nucleotide binding protein 5' (GIMAP5). Mechanisms underlying the pro-survival function of GIMAP5 in T lymphocytes are unclear. Overexpression studies have shown that GIMAP5 localizes within mitochondria and the endoplasmic reticulum (ER). We have used an antiserum raised against GIMAP5 to define its localization in rat primary T lymphocytes. We present evidence that endogenous GIMAP5 is associated with a sedimentable subcellular fraction that is distinct from mitochondria and the ER. These data are further supported by confocal microscopy using a GIMAP5 construct with an intact C-terminal membrane anchor. Nonetheless, T cells isolated from GIMAP5(lyp/lyp) rats display rapid loss of mitochondrial membrane potential. Our findings suggest that GIMAP5 regulates T lymphocyte survival by mechanisms that operate upstream of mitochondria.
T淋巴细胞的自发凋亡导致生物繁殖型糖尿病易感（BB-DP）大鼠出现明显的淋巴细胞减少，进而引发自身免疫性1型糖尿病。这些大鼠的淋巴细胞减少表型与lyp基因座有关。lyp等位基因在编码“免疫相关核苷酸结合蛋白5的GTP酶”（GIMAP5）的基因内存在移码突变。GIMAP5在T淋巴细胞中促生存功能的潜在机制尚不清楚。过表达研究表明，GIMAP5定位于线粒体和内质网（ER）内。我们使用针对GIMAP5产生的抗血清来确定其在大鼠原代T淋巴细胞中的定位。我们提供的证据表明，内源性GIMAP5与一种可沉降的亚细胞组分相关，该组分与线粒体和内质网不同。使用具有完整C末端膜锚定的GIMAP5构建体进行的共聚焦显微镜检查进一步支持了这些数据。尽管如此，从GIMAP5(lyp/lyp)大鼠分离的T细胞显示出线粒体膜电位的快速丧失。我们的研究结果表明，GIMAP5通过在线粒体上游起作用的机制调节T淋巴细胞的存活。
