Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance Is Crucial for Renal Endocytosis
Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance Is Crucial for Renal Endocytosis
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DOI：
10.1126/science.1188070
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发表时间：
2010-06-11
期刊：
影响因子：
56.9
通讯作者：
Jentsch, Thomas J.
中科院分区：
文献类型：
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作者：
Novarino, Gaia;Weinert, Stefanie;Jentsch, Thomas J.
内体阴离子转运蛋白ClC-5的缺失损害了肾脏的内吞作用，是人类登特氏病的基础。ClC-5被认为通过中和质子泵电流促进内体酸化，从而促进内吞作用。然而，ClC-5是2氯(氯(-))/质子(H(+))交换，而不是氯(-)通道。我们产生了携带解偶联E211A(UNC)突变的小鼠，该突变将ClC-5转化为纯Cl(-)导体。CLC-5基因被敲除的小鼠肾内三磷酸腺苷(ATP)依赖的酸化减少，而Clcn5(UNC)小鼠则正常。然而，它们的近端小管内吞功能也受到了损害。因此，ClC-5用H(+)-ATPase积累的质子来换取内体氯浓度，可能在内吞作用中起作用。
Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent's disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl(-))/proton (H(+)) exchanger rather than a Cl(-) channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl(-) conductor. Adenosine triphosphate (ATP)-dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5(unc) mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H(+)-ATPase, may play a role in endocytosis.