PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation
PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation
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DOI：
10.1093/hmg/ddp463
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Walz, Gerd
中科院分区：
文献类型：
--
作者：
Gao, Hongyu;Wang, Yan;Walz, Gerd
常染色体显性遗传性多囊肝病（PCLD）是由PRKCSH或Sec 63（两种与内质网（ER）相关的蛋白质）突变引起的。这两种蛋白质都参与新合成糖蛋白的碳水化合物加工、折叠和易位。据推测，蛋白质的质量控制缺陷启动内质网相关降解（ERAD），这破坏了PRKCSH或Sec 63突变患者的肝脏稳态。然而，确切的分子机制尚不清楚。在这里，我们表明，在斑马鱼胚胎中PRKCSH的过度表达或耗尽导致前肾囊肿，异常的身体弯曲和位置倒置。相同的表型变化由TRPP 2的耗竭或过度表达诱导。PRKCSH水平的增加改善了由过度表达TRPP 2引起的发育异常，而过量的TRPP 2可以补偿PRKCSH的损失，表明这些蛋白质共享共同的信号传导途径。PRKCSH结合TRPP 2的C-末端结构域，并且两种蛋白质在ER内共定位。此外，PRKCSH与Herp相互作用，并抑制Herp介导的TRPP 2泛素化。我们的研究结果表明，PRKCSH作为一种分子伴侣样分子，防止ERAD的TRPP 2。TRPP 2和PRKCSH之间的失衡可能导致PRKCSH突变的PCLD患者的囊肿形成，从而解释了PCLD和常染色体显性多囊肾病中观察到的重叠表现。
Autosomal dominant polycystic liver disease (PCLD) is caused by mutations of either PRKCSH or Sec63, two proteins associated with the endoplasmic reticulum (ER). Both proteins are involved in carbohydrate processing, folding and translocation of newly synthesized glycoproteins. It is postulated that defective quality control of proteins initiates endoplasmic reticulum-associated degradation (ERAD), which disrupts hepatic homeostasis in patients with PRKCSH or Sec63 mutations. However, the precise molecular mechanisms are not known. Here, we show that over-expression or depletion of PRKCSH in zebrafish embryos leads to pronephric cysts, abnormal body curvature and situs inversus. Identical phenotypic changes are induced by depletion or over-expression of TRPP2. Increased PRKCSH levels ameliorate developmental abnormalities caused by over-expressed TRPP2, whereas excess TRPP2 can compensate the loss PRKCSH, indicating that the proteins share a common signaling pathway. PRKCSH binds the C-terminal domain of TRPP2, and both proteins co-localize within the ER. Furthermore, PRKCSH interacts with Herp, and inhibits Herp-mediated ubiquitination of TRPP2. Our findings suggest that PRKCSH functions as a chaperone-like molecule, which prevents ERAD of TRPP2. Dysequilibrium between TRPP2 and PRKCSH may lead to cyst formation in PCLD patients with PRKCSH mutations, and thereby account for the overlapping manifestations observed in PCLD and autosomal dominant polycystic kidney disease.