SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway
SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway
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SNX9 通过激活 Hippo-YAP 信号通路抑制常染色体显性多囊肾病的细胞增殖和囊肿发育
DOI：
10.3389/fcell.2020.00811
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发表时间：
2020-08
影响因子：
5.5
通讯作者：
Sheng-Qiang Yu
中科院分区：
文献类型：
--
作者：
Ai-Wen Shen;Li-Li Fu;Lu Lin;Bo Sun;Dong-Xu Song;Wu-Tao Wang;Yi-Hao Wang;Pei-Ran Yin;Sheng-Qiang Yu
常染色体显性遗传性多囊肾病（autosomaldominantpolycystickidney disease，ADPKD）是一个涉及多个基因和信号通路改变的复杂过程，其发病机制尚不清楚。在这里，我们证明了分选连接蛋白9（SNX 9）在ADPKD发展过程中的抑制作用。在ADPKD患者的肾组织中首次检测到分选连接蛋白9的表达，并且在Pkd 1敲除（Pkd 1-/-）和对照小鼠中也检测到SNX 9的表达。随后，进行了一系列功能获得和丧失研究，以探索SNX 9在ADPKD进展中的生物学作用和潜在的分子机制。与对照个体和野生型小鼠（Pkd 1 +/+）相比，ADPKD患者和Pkd 1-/-小鼠中SNX 9的表达分别显著下调。SNX 9的异位表达显著抑制ADPKD细胞增殖、肾囊肿形成和扩大，而SNX 9沉默促进了这些作用。从机制上讲，我们发现SNX 9直接与yes相关蛋白（雅普）相互作用，并增加了大肿瘤抑制激酶1介导的雅普磷酸化，导致雅普的细胞质滞留，雅普/TEA结构域转录因子4复合物的转录活性降低，从而抑制Hippo靶基因表达和ADPKD的发展。总之，我们的研究结果为SNX 9在ADPKD发病机制中发挥的作用提供了新的见解，并可能揭示ADPKD和相关肾脏疾病的新治疗方法。
Autosomal dominant polycystic kidney disease (ADPKD) is a complex process, involving the alteration of multiple genes and signaling pathways, and the pathogenesis of ADPKD remains largely unknown. Here, we demonstrated the suppressive role of sorting nexin 9 (SNX9) during ADPKD development. Sorting nexin 9 expression was detected in the kidney tissues of ADPKD patients, for the first time, and SNX9 expression was also detected in Pkd1 knockout (Pkd1–/–) and control mice. Subsequently, a series of gain- and loss-of-function studies were performed, to explore the biological roles and underlying molecular mechanisms of SNX9 in ADPKD progression. The expression of SNX9 was significantly downregulated in ADPKD patients and Pkd1–/– mice compared with control individuals and wild-type mice (Pkd1+/+), respectively. The ectopic expression of SNX9 significantly inhibited ADPKD cell proliferation, renal cyst formation and enlargement, whereas these effects were promoted by SNX9 silencing. Mechanistically, we found that SNX9 interacted directly with yes-associated protein (YAP) and increased the large tumor suppressor kinase 1-mediated phosphorylation of YAP, resulting in the cytoplasmic retention of YAP, the decreased transcriptional activity of the YAP/TEA domain transcription factor 4 complex, and, consequently, the inhibition of Hippo target gene expression and ADPKD development. Taken together, our findings provided novel insights into the role played by SNX9 during ADPKD pathogenesis and may reveal novel therapeutic approaches for ADPKD and related kidney diseases.
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影响因子：
19
作者：
Bendris N;Schmid SL
通讯作者：
Schmid SL
DOI：
10.1016/j.trsl.2014.11.003
发表时间：
2015-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
LaRiviere WB;Irazabal MV;Torres VE
通讯作者：
Torres VE
Hippo 通路在器官大小控制、组织稳态和癌症中的作用
影响因子：
64.5
作者：
Yu FX;Zhao B;Guan KL
通讯作者：
Guan KL
影响因子：
4.6
作者：
Sasaki Y;Hidaka T;Ueno T;Akiba-Takagi M;Oliva Trejo JA;Seki T;Nagai-Hosoe Y;Tanaka E;Horikoshi S;Tomino Y;Suzuki Y;Asanuma K
通讯作者：
Asanuma K
模拟 VGLL4 功能的肽作为 YAP 拮抗剂治疗胃癌
影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai