Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway
Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway
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Scribble 通过调节 Hippo 信号通路影响常染色体显性多囊肾病的囊肿形成
DOI：
10.1096/fj.201701376rr
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Mei Changlin
中科院分区：
文献类型：
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作者：
Xu Dechao;Lv Jiayi;He Liangliang;Fu Lili;Hu Ruikun;Cao Ying;Mei Changlin
极性复合体，包括 PAR（分区缺陷）、CRB（碎屑）和 SCRIB（涂鸦）复合体，是功能性顶端基底外侧极性的生理建立、稳定和维持所必需的。一些极性复合物的失活会导致囊性肾，并且在常染色体显性多囊肾病（ADPKD）中经常观察到顶端-基底外侧极性缺陷；然而，人们对极性复合物在 ADPKD 中的作用知之甚少。在这里，我们证明了 SCRIB 复合物的核心蛋白 Scribble 在 ADPKD 细胞系和该疾病的斑马鱼模型（pkd2morphants）中下调。 Scribble 的过度表达可以减少 pkd2 形态体中囊肿的形成，以及斑马鱼扩张前肾管的 Scribble 的丢失。此外，Hippo信号通路在scribmutants和pkd2morphants中失活，其中生理上位于细胞质的Yes相关蛋白（YAP）被易位到细胞核。值得注意的是，细胞质 YAP（而不是细胞核 YAP）的过度表达可以减少 pkd2morphants 中的囊肿形成。一致的是，敲除 ya 导致斑马鱼出现囊性肾，通过细胞质 YAP 的过度表达（而非细胞核 YAP）来挽救囊性肾。最后，Scribandyaphad 在囊肿形成过程中与 pkd2 存在遗传相互作用，Scribble 的过表达减弱了 ADPKD 中细胞质 YAP 的下调。总而言之，我们的数据表明，Scribble 诱导 YAP 磷酸化，从而通过介导 YAP 核质穿梭影响 ADPKD 中囊肿的形成。—Xu, D.、Lv, J.、He, L.、Fu, L.、Hu, R.、Cao, Y.、Mei, C. Scribble 通过调节 Hippo 信号通路影响常染色体显性多囊肾病的囊肿形成。FASEB J. 32, 4394–4407 (2018)。 www.fasebj.org
Polarity complexes, including the PAR (Partitioning‐defective), CRB (Crumbs) and SCRIB (Scribble) complexes, are required for the physiologic establishment, stabilization, and maintenance of a functional apical‐basolateral polarity. Inactivation of some of the polarity complexes results in cystic kidneys, and apical‐basolateral polarity defects are commonly observed in autosomal‐dominant polycystic kidney disease (ADPKD); however, little is known about the role that polarity complexes play in ADPKD. Here, we demonstrate that Scribble, a core protein of the SCRIB complex, is down‐regulated in ADPKD cell lines and the zebrafish model of this disease(pkd2mor‐phants). Overexpression of Scribble could reduce cyst formation inpkd2morphants, and loss ofscribled to a dilated pronephric duct in zebrafish. Furthermore, the Hippo signaling pathway was inactivated inscribmutants andpkd2morphants in which Yes‐associated protein (YAP), which is physiologically locatedinthe cytoplasm, was translocated to the nucleus. Of note, overexpression of cytoplasmic YAP, instead of nuclear YAP, could reduce cyst formation inpkd2morphants. Consistently, knockout ofyapresulted in cystic kidneys in zebrafish, which was rescued by the overexpression of cytoplasmic YAP, but not nuclear YAP. Finally,scribandyaphad a genetic interaction withpkd2in cyst formation, and the overexpression of Scribble attenuated the down‐regulation of cytoplasmic YAP in ADPKD. Altogether, our data indicate that Scribble induces the phosphorylation of YAP and, consequently, influences cyst formation in ADPKD by mediating YAP nucleocytoplasmic shuttling.—Xu, D., Lv, J., He, L., Fu, L., Hu, R., Cao, Y., Mei, C. Scribble influences cyst formation in autosomal‐dominant polycystic kidney disease by regulating Hippo signaling pathway.FASEB J. 32, 4394–4407 (2018). www.fasebj.org