Plasmin Activates Epithelial Na+ Channels by Cleaving the γ Subunit
Plasmin Activates Epithelial Na+ Channels by Cleaving the γ Subunit
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DOI：
10.1074/jbc.m805676200
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发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Kleyman, Thomas R.
中科院分区：
文献类型：
--
作者：
Passero, Christopher J.;Mueller, Gunhild M.;Kleyman, Thomas R.
上皮钠通道（ENaC）亚基的蛋白水解加工随着通道在生物合成途径内成熟而发生。α和γ亚基的蛋白水解加工事件与通道激活相关。弗林蛋白酶在两个位点切割α亚基胞外域，释放抑制性通道并激活通道。然而，弗林蛋白酶仅切割γ亚基胞外域一次。需要由其他蛋白酶（例如前列腺素和弹性蛋白酶）诱导的γ亚基中的第二远端切割来释放第二抑制束并进一步激活通道。我们发现丝氨酸蛋白酶纤溶酶激活ENaC与诱导γ亚基在γ Lys（194）处的裂解有关，γ Lys（194）是弗林蛋白酶位点远端的位点。γ K194A突变体阻止ENaC的纤溶酶依赖性激活和独特的70 kDa羧基末端γ亚基切割片段的纤溶酶依赖性产生。ENaC的纤溶酶依赖性切割和活化可能在与蛋白尿相关的人类疾病中的细胞外体积扩张中起作用，因为过滤的纤溶酶原可以被尿激酶加工，从肾小管上皮细胞释放，以产生活性纤溶酶。
Proteolytic processing of epithelial sodium channel ( ENaC) subunits occurs as channels mature within the biosynthetic pathway. The proteolytic processing events of the alpha and gamma subunits are associated with channel activation. Furin cleaves the alpha subunit ectodomain at two sites, releasing an inhibitory tract and activating the channel. However, furin cleaves the gamma subunit ectodomain only once. A second distal cleavage in the gamma subunit induced by other proteases, such as prostasin and elastase, is required to release a second inhibitory tract and further activate the channel. We found that the serine protease plasmin activates ENaC in association with inducing cleavage of the gamma subunit at gamma Lys(194), a site distal to the furin site. A gamma K194A mutant prevented both plasmin-dependent activation of ENaC and plasmin-dependent production of a unique 70-kDa carboxyl-terminal gamma subunit cleavage fragment. Plasmin-dependent cleavage and activation of ENaC may have a role in extracellular volume expansion in human disorders associated with proteinuria, as filtered plasminogen may be processed by urokinase, released from renal tubular epithelium, to generate active plasmin.