The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics
The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics
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DOI：
10.1074/jbc.m117.819029
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发表时间：
2017-12-22
影响因子：
4.8
通讯作者：
Campbell, Kirk N.
中科院分区：
文献类型：
--
作者：
Meliambro, Kristin;Wong, Jenny S.;Campbell, Kirk N.
肾足细胞是肾小球滤过屏障的重要组成部分。确定足细胞损伤和存活的分子机制对于更好地理解和管理肾脏疾病非常重要。KIBRA（肾脑蛋白）是由Wwc1基因编码的Hippo信号通路的上游调节因子，在果蝇和MCF10A细胞中，KIBRA具有其推定的结合伙伴树突蛋白的促损伤特性，并拮抗下游Hippo信号通路效应因子YAP（叶氏相关蛋白）的促存活信号。我们最近发现YAP是肾小球滤过屏障的重要组成部分，通过抑制树突蛋白促凋亡功能促进足细胞存活。尽管最近取得了这些进展，介导足细胞损伤的信号通路仍然知之甚少。在这里，我们测试了假设，类似于它在其他模型系统中的作用，KIBRA促进足细胞损伤。我们发现KIBRA和磷酸化YAP蛋白在活检证实的局灶节段性肾小球硬化（FSGS）患者的肾小球中表达增加。KIBRA/WWc1在小鼠足细胞中的过表达可促进LATS激酶磷酸化，导致随后的YAP Ser-127磷酸化、YAP细胞质隔离和YAP靶基因表达降低。在功能上，KIBRA过表达诱导足细胞发生了显著的形态学变化，包括肌动蛋白细胞骨架结构的破坏和局灶黏附大小和数量的减少，所有这些都被随后的YAP过表达所挽救。相反，KIBRA敲除小鼠在基线时表现出磷酸化的YAP减少和YAP表达增加。这些小鼠在硫酸鱼精蛋白灌注后可防止急性足细胞足突消失。KIBRA敲低的足细胞也能免受蛋白蛋白引起的损伤。这些发现提示KIBRA在足细胞损伤的发病机制和蛋白尿肾病的进展中起重要作用。
Kidney podocytes represent a key constituent of the glomerular filtration barrier. Identifying the molecular mechanisms of podocyte injury and survival is important for better understanding and management of kidney diseases. KIBRA (kidney brain protein), an upstream regulator of the Hippo signaling pathway encoded by the Wwc1 gene, shares the pro-injury properties of its putative binding partner dendrin and antagonizes the pro-survival signaling of the downstream Hippo pathway effector YAP (Yes-associated protein) in Drosophila and MCF10A cells. We recently identified YAP as an essential component of the glomerular filtration barrier that promotes podocyte survival by inhibiting dendrin pro-apoptotic function. Despite these recent advances, the signaling pathways that mediate podocyte injury remain poorly understood. Here we tested the hypothesis that, similar to its role in other model systems, KIBRA promotes podocyte injury. We found increased expression of KIBRA and phosphorylated YAP protein in glomeruli of patients with biopsy-proven focal segmental glomerulosclerosis (FSGS). KIBRA/WWc1 overexpression in murine podocytes promoted LATS kinase phosphorylation, leading to subsequent YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. Functionally, KIBRA overexpression induced significant morphological changes in podocytes, including disruption of the actin cytoskeletal architecture and reduction of focal adhesion size and number, all of which were rescued by subsequent YAP overexpression. Conversely, constitutive KIBRA knockout mice displayed reduced phosphorylated YAP and increased YAP expression at baseline. These mice were protected from acute podocyte foot process effacement following protamine sulfate perfusion. KIBRA knockdown podocytes were also protected against protamine-induced injury. These findings suggest an important role for KIBRA in the pathogenesis of podocyte injury and the progression of proteinuric kidney disease.