Proteolytic cleavage of Podocin by Matriptase exacerbates podocyte injury
Proteolytic cleavage of Podocin by Matriptase exacerbates podocyte injury
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DOI：
10.1074/jbc.ra120.013721
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发表时间：
2020-09
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通讯作者：
Shota Ozawa;Masaya Matsubayashi;H. Nanaura;M. Yanagita;K. Mori;K. Asanuma;N. Kajiwara;K. Hayashi;H. Ohashi;M. Kasahara;H. Yokoi;H. Kataoka;Eiichiro Mori;T. Nakagawa
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作者：
Shota Ozawa;Masaya Matsubayashi;H. Nanaura;M. Yanagita;K. Mori;K. Asanuma;N. Kajiwara;K. Hayashi;H. Ohashi;M. Kasahara;H. Yokoi;H. Kataoka;Eiichiro Mori;T. Nakagawa
足细胞损伤是肾脏疾病进展的关键步骤，并且通常与包括Podocin在内的狭缝隔膜蛋白的损失有关。虽然有一种可能性，这些狭缝隔膜蛋白质的细胞外结构域可以是一个病理性蛋白水解的目标，驱动现象的精确机制仍然未知。在这里，我们发现间质蛋白酶，一种膜锚定蛋白，在CKD患者和小鼠的足细胞中被激活，而间质蛋白酶抑制剂减缓了小鼠肾脏疾病的进展。该机制可以通过有利于间质蛋白酶超过其同源抑制剂肝细胞生长因子激活物抑制剂1型（HAI-1）的不平衡来解释，因为足细胞中HAI-1的条件性消耗加速了小鼠模型中的足细胞损伤。间质蛋白酶能够切割Podocin，但这种反应被HAI-1或显性负性间质蛋白酶阻断。此外，Podocin的N末端，作为间质蛋白酶切割Podocin的结果，易位到核仁，表明Podocin的N末端可能参与足细胞损伤的过程。鉴于这些观察结果，我们提出间质蛋白酶对Podocin的蛋白水解裂解可能会导致足细胞损伤，靶向间质蛋白酶可能是CKD患者的新治疗策略。
Podocyte injury is a critical step toward the progression of renal disease and is often associated with a loss of slit diaphragm proteins, including Podocin. Although there is a possibility that the extracellular domain of these slit diaphragm proteins can be a target for a pathological proteolysis, the precise mechanism driving the phenomenon remains unknown. Here we show that Matriptase, a membrane-anchored protein, was activated at podocytes in CKD patients and mice, whereas Matriptase inhibitors slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), because conditional depletion of HAI-1 in podocytes accelerated podocyte injury in mouse model. Matriptase was capable of cleaving Podocin, but such a reaction was blocked by either HAI-1 or dominant-negative Matriptase. Furthermore, the N terminus of Podocin, as a consequence of Matriptase cleavage of Podocin, translocated to nucleoli, suggesting that the N terminus of Podocin might be involved in the process of podocyte injury. Given these observations, we propose that the proteolytic cleavage of Podocin by Matriptase could potentially cause podocyte injury and that targeting Matriptase could be a novel therapeutic strategy for CKD patients.