Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC‐7
Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC‐7
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DOI：
10.1096/fj.09-130880
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Lena Wartosch;J. Fuhrmann;M. Schweizer;T. Stauber;T. Jentsch
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作者：
Lena Wartosch;J. Fuhrmann;M. Schweizer;T. Stauber;T. Jentsch
ClC-7（CLC家族氯离子通道和转运蛋白的晚期内体/溶酶体成员）或其β亚基Ostm 1的突变可导致小鼠和人类的骨硬化症和溶酶体贮积病。严重表型的小鼠整体删除ClC-7或Ostm 1和缺乏存储材料在培养的细胞阻碍了解释的机制，导致溶酶体病理学在缺乏功能性ClC-7/Ostm 1转运蛋白。组织特异性ClC-7敲除小鼠现在揭示，储存物质的积累在缺乏ClC-7的神经元或肾近端小管细胞中以细胞自发方式发生。几乎所有缺乏ClC 7的神经元都会死亡。胶质细胞的激活仅限于ClC-7失活的大脑区域。在显示高胞内活性的肾近端小管细胞中研究了ClC-7破坏对溶酶体功能的影响。在近端小管中携带ClC-7嵌合缺失的小鼠的体内脉冲追踪内吞实验允许直接比较表达或缺乏ClC-7的细胞之间内吞蛋白的处理。尽管蛋白质在两种基因型的细胞中的内吞相似，但其半衰期在ClC-7缺陷细胞中显着延长。这些实验表明，溶酶体病理是ClC-7破坏的细胞自主后果，ClC-7对溶酶体蛋白降解很重要。瓦托施湖Fuhrmann，J. C.，Schweizer，M.，Stauber，T.，Jentsch，T.内吞蛋白的溶酶体降解取决于氯转运蛋白ClC-7。FASEB J.23，4056 - 4068（2009）. www.fasebj.org
Mutations in either ClC‐7, a late endoso‐ mal/lysosomal member of the CLC family of chloride channels and transporters, or in its β‐subunit Ostm1 cause osteopetrosis and lysosomal storage disease in mice and humans. The severe phenotype of mice globally deleted for ClC‐7 or Ostm1 and the absence of storage material in cultured cells hampered investiga‐ tions of the mechanism leading to lysosomal pathology in the absence of functional ClC‐7/Ostm1 transporters. Tissue‐specific ClC‐7‐knockout mice now reveal that accumulation of storage material occurs cell‐autono‐ mously in neurons or renal proximal tubular cells lacking ClC‐7. Almost all ClC‐7‐deficient neurons die. The activation of glia is restricted to brain regions where ClC‐7 has been inactivated. The effect of ClC‐7 disruption on lysosomal function was investigated in renal proximal tubular cells, which display high endo‐ cytotic activity. Pulse‐chase endocytosis experiments in vivo with mice carrying chimeric deletion of ClC‐7 in proximal tubules allowed a direct comparison of the handling of endocytosed protein between cells express‐ ing or lacking ClC‐7. Whereas protein was endocytosed similarly in cells of either genotype, its half‐life in‐ creased significantly in ClC‐7‐deficient cells. These ex‐ periments demonstrate that lysosomal pathology is a cell‐autonomous consequence of ClC‐7 disruption and that ClC‐7 is important for lysosomal protein degrada‐ tion.—Wartosch, L., Fuhrmann, J. C., Schweizer, M., Stauber, T., Jentsch, T. J. Lysosomal degradation of endocytosed proteins depends on the chloride trans‐ port protein ClC‐7. FASEB J. 23, 4056 – 4068 (2009). www.fasebj.org