Yang Mei-Ling, Doyle Hester A, Gee Renelle J, Lowenson Jonathan D, Clarke Steven, Lawson Brian R, Aswad Dana W, Mamula Mark J
Section of Rheumatology, Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
J Immunol. 2006 Oct 1;177(7):4541-9. doi: 10.4049/jimmunol.177.7.4541.
Posttranslational protein modifications influence a number of immunologic responses ranging from intracellular signaling to protein processing and presentation. One such modification, termed isoaspartyl (isoAsp), is the spontaneous nonenzymatic modification of aspartic acid residues occurring at physiologic pH and temperature. In this study, we have examined the intracellular levels of isoAsp residues in self-proteins from MRL(+/+), MRL/lpr, and NZB/W F(1) mouse strains compared with nonautoimmune B10.BR mice. In contrast to control B10.BR or NZB/W mice, the isoAsp content in MRL autoimmune mice increased and accumulated with age in erythrocytes, brain, kidney, and T lymphocytes. Moreover, T cells that hyperproliferate to antigenic stimulation in MRL mice also have elevated intracellular isoAsp protein content. Protein l-isoaspartate O-methyltransferase activity, a repair enzyme for isoAsp residues in vivo, remains stable with age in all strains of mice. These studies demonstrate a role for the accumulation of intracellular isoAsp proteins associated with T cell proliferative defects of MRL autoimmune mice.
蛋白质翻译后修饰影响多种免疫反应，从细胞内信号传导到蛋白质加工和呈递。其中一种修饰称为异天冬氨酸（isoAsp），是在生理pH和温度下天冬氨酸残基发生的自发非酶促修饰。在本研究中，我们检测了与非自身免疫性B10.BR小鼠相比，MRL(+/+)、MRL/lpr和NZB/W F(1)小鼠品系自身蛋白质中异天冬氨酸残基的细胞内水平。与对照B10.BR或NZB/W小鼠不同，MRL自身免疫小鼠红细胞、脑、肾和T淋巴细胞中的异天冬氨酸含量随年龄增加而升高并积累。此外，在MRL小鼠中对抗原刺激过度增殖的T细胞其细胞内异天冬氨酸蛋白质含量也升高。蛋白质L-异天冬氨酸O-甲基转移酶活性是体内异天冬氨酸残基的修复酶，在所有小鼠品系中随年龄保持稳定。这些研究证明了细胞内异天冬氨酸蛋白质积累与MRL自身免疫小鼠T细胞增殖缺陷有关。
