A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
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常染色体显性多囊性肝病由PRKCSH或SEC63突变引起。葡萄糖苷酶IIβ和SEC63p分别在内质网的蛋白质易位和质量控制途径中起作用。本研究表明，小鼠需要葡萄糖苷酶IIα和Sec63p才能充分表达多囊肾病基因产物多囊蛋白-1和多囊蛋白-2的功能复合物。我们发现多囊蛋白-1是该复合体的限速成分，并且在Prkcsh或Sec63突变后，囊性扩张和功能多囊蛋白-1水平之间存在剂量-反应关系。多囊蛋白-1的表达减少也有助于肾脏对隐性多囊肾病基因Pkhd1突变导致的囊肿形成敏感。最后，我们发现在缺乏葡萄糖苷酶IIβ的细胞中，蛋白酶体抑制增加了多囊素-1的稳态水平，并且在人类常染色体显性多囊性肝病的同源基因模型中，用蛋白酶体抑制剂治疗可以减少囊性疾病。
Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIα and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.
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