Cathepsin E deficiency induces a novel form of lysosomal storage disorder showing the accumulation of lysosomal membrane sialoglycoproteins and the elevation of lysosomal pH in macrophages
Cathepsin E deficiency induces a novel form of lysosomal storage disorder showing the accumulation of lysosomal membrane sialoglycoproteins and the elevation of lysosomal pH in macrophages
复制标题
DOI：
10.1074/jbc.m604143200
复制
发表时间：
2007-01-19
影响因子：
4.8
通讯作者：
Yamamoto, Kenji
中科院分区：
文献类型：
--
作者：
Yanagawa, Michiyo;Tsukuba, Takayuki;Yamamoto, Kenji
组织蛋白酶 E 是一种主要在免疫系统细胞中表达的内溶酶体天冬氨酸蛋白酶，在免疫反应中具有重要作用。然而，人们对组织蛋白酶 E 在该系统中的确切作用知之甚少。在这里，我们报道组织蛋白酶 E 缺乏 (CatE(-/-)) 会导致巨噬细胞中一种新型的溶酶体储存障碍，表现为两种主要的溶酶体膜唾液酸糖蛋白 LAMP-1 和 LAMP-2 的积累以及溶酶体 pH 值的升高。这些显着的特征也在用胃酶抑素 A 和蛔虫抑制剂处理的野生型巨噬细胞中发现。虽然野生型和CatE(-/-)巨噬细胞之间的表达、生物合成和运输没有明显差异，但由于组织蛋白酶E缺乏，这两种膜蛋白的降解率明显降低。由于两种细胞类型中的液泡型H+-ATP酶活性没有差异，因此CatE(-/-)巨噬细胞中溶酶体pH升高很可能是由于这些被酸性单糖高度修饰的溶酶体膜糖蛋白的积累，从而导致控制溶酶体pH的非质子因子的破坏。此外，通过用纯化的组织蛋白酶 E 在 pH 5 下处理从野生型巨噬细胞分离的溶酶体膜部分，也观察到了 LAMP-1 和 LAMP-2 以及 LIMP-2 的选择性降解。因此，我们的结果表明，组织蛋白酶 E 对于防止这些溶酶体膜唾液酸糖蛋白的积累非常重要，而这些糖蛋白可诱导一种新形式的溶酶体贮积症。
Cathepsin E, an endolysosomal aspartic proteinase predominantly expressed in cells of the immune system, has an important role in immune responses. However, little is known about the precise roles of cathepsin E in this system. Here we report that cathepsin E deficiency (CatE(-/-)) leads to a novel form of lysosome storage disorder in macrophages, exhibiting the accumulation of the two major lysosomal membrane sialoglycoproteins LAMP-1 and LAMP-2 and the elevation of lysosomal pH. These striking features were also found in wild-type macrophages treated with pepstatin A and Ascaris inhibitor. Whereas there were no obvious differences in their expression, biosynthesis, and trafficking between wild-type and CatE(-/-) macrophages, the degradation rates of these two membrane proteins were apparently decreased as a result of cathepsin E deficiency. Because there was no difference in the vacuolar-type H+ -ATPase activity in both cell types, the elevated lysosomal pH in CatE(-/-) macrophages is most likely due to the accumulation of these lysosomal membrane glycoproteins highly modified with acidic monosaccharides, thereby leading to the disruption of non-proton factors controlling lysosomal pH. Furthermore, the selective degradation of LAMP-1 and LAMP-2, as well as LIMP-2, was also observed by treatment of the lysosomal membrane fraction isolated from wild-type macrophages with purified cathepsin E at pH 5. Our results thus suggest that cathepsin E is important for preventing the accumulation of these lysosomal membrane sialoglycoproteins that can induce a new form of lysosomal storage disorder.