Ilangumaran Subburaj, Forand-Boulerice Melissa, Bousquet Simon M, Savard Alexandre, Rocheleau Philippe, Chen Xi Lin, Dupuis Gilles, Poussier Philippe, Boulay Guylain, Ramanathan Sheela
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Québec, Canada.
Mol Immunol. 2009 Mar;46(6):1256-9. doi: 10.1016/j.molimm.2008.09.031. Epub 2008 Nov 12.
The recessive lyp allele, which harbors a defective gimap5 (GTPase of immunity-associated nucleotide binding protein 5) gene, causes spontaneous apoptosis of T lymphocytes in the biobreeding diabetes-prone strain of rats. Mechanisms underlying the pro-survival function of GIMAP5 remain unclear. In this study, we show that gimap5(lyp/lyp) T cells display diminished calcium flux in response to thapsigargin or signaling via the T cell antigen receptor. This defect is manifested in mature single positive thymocytes, where the survival defect first occurs. We also show that GIMAP5 deficiency does not affect the thapsigargin-induced calcium release from the intracellular stores but impairs subsequent calcium entry across the plasma membrane. Our findings suggest that GIMAP5 is an important regulator of calcium response in T lymphocytes and impaired calcium signaling might underlie spontaneous apoptosis of gimap5(lyp/lyp) T cells.
隐性lyp等位基因携带缺陷型gimap5（免疫相关核苷酸结合蛋白5的GTP酶）基因，可导致生物繁殖糖尿病易患大鼠品系中的T淋巴细胞发生自发性凋亡。GIMAP5促生存功能的潜在机制尚不清楚。在本研究中，我们发现gimap5(lyp/lyp) T细胞对毒胡萝卜素或通过T细胞抗原受体的信号传导反应时，钙通量降低。这种缺陷在成熟的单阳性胸腺细胞中表现出来，而生存缺陷首先在这些细胞中出现。我们还表明，GIMAP5缺陷并不影响毒胡萝卜素诱导的细胞内钙库释放钙，但会损害随后的钙跨质膜内流。我们的研究结果表明，GIMAP5是T淋巴细胞钙反应的重要调节因子，钙信号受损可能是gimap5(lyp/lyp) T细胞自发性凋亡的基础。
