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A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation

Nature Genetics volume 43, pages 639–647 (2011)Cite this article

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Abstract

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 IIβ 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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Figure 1: Pkd1 dosage is the main genetic determinant of Prkcsh-dependent cyst formation.
Figure 2: Pkd1 and Pkd2 dosage in Sec63-dependent cyst formation.
Figure 3: Impaired biogenesis and trafficking of PC1 in ADPLD.
Figure 4: Late stage tubule dilation in Prkcsh and Sec63 mutant kidneys overexpressing PC1 (a,b).
Figure 5: Nephron segment-specific sensitivity to Pkd1 dosage-dependent proliferation and cyst growth.
Figure 6: Genetic interaction of Pkhd1, Pkd1 and Sec63.
Figure 7: Proteasome inhibitor therapy ameliorates cyst formation following loss of Prkcsh.

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References

  1. Qian, Q. et al. Clinical profile of autosomal dominant polycystic liver disease. Hepatology 37, 164–171 (2003).

    Article  Google Scholar 

  2. Reynolds, D.M. et al. Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am. J. Hum. Genet. 67, 1598–1604 (2000).

    Article  CAS  Google Scholar 

  3. Li, A. et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72, 691–703 (2003).

    Article  CAS  Google Scholar 

  4. Davila, S. et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat. Genet. 36, 575–577 (2004).

    Article  CAS  Google Scholar 

  5. Drenth, J.P., Te Morsche, R.H., Smink, R., Bonifacino, J.S. & Jansen, J.B. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat. Genet. 33, 345–347 (2003).

    Article  CAS  Google Scholar 

  6. Lyman, S.K. & Schekman, R. Binding of secretory precursor polypeptides to a translocon subcomplex is regulated by BiP. Cell 88, 85–96 (1997).

    Article  CAS  Google Scholar 

  7. Young, B.P., Craven, R.A., Reid, P.J., Willer, M. & Stirling, C.J. Sec63p and Kar2p are required for the translocation of SRP-dependent precursors into the yeast endoplasmic reticulum in vivo. EMBO J. 20, 262–271 (2001).

    Article  CAS  Google Scholar 

  8. Misselwitz, B., Staeck, O., Matlack, K.E. & Rapoport, T.A. Interaction of BiP with the J-domain of the Sec63p component of the endoplasmic reticulum protein translocation complex. J. Biol. Chem. 274, 20110–20115 (1999).

    Article  CAS  Google Scholar 

  9. Trombetta, E.S., Simons, J.F. & Helenius, A. Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit. J. Biol. Chem. 271, 27509–27516 (1996).

    Article  CAS  Google Scholar 

  10. Trombetta, E.S., Fleming, K.G. & Helenius, A. Quaternary and domain structure of glycoprotein processing glucosidase II. Biochemistry 40, 10717–10722 (2001).

    Article  CAS  Google Scholar 

  11. Helenius, A. & Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73, 1019–1049 (2004).

    Article  CAS  Google Scholar 

  12. Stigliano, I.D., Caramelo, J.J., Labriola, C.A., Parodi, A.J. & D'Alessio, C. Glucosidase II β subunit modulates N-glycan trimming in fission yeasts and mammals. Mol. Biol. Cell 20, 3974–3984 (2009).

    Article  CAS  Google Scholar 

  13. The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosme 16. Cell 77, 881–894 (1994).

    Article  Google Scholar 

  14. The International Polycystic Kidney Disease Consortium. Polycystic kidney disease: The complete structure of the PKD1 gene and its protein. Cell 81, 289–298 (1995).

  15. Mochizuki, T. et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339–1342 (1996).

    Article  CAS  Google Scholar 

  16. Pazour, G.J., San Agustin, J.T., Follit, J.A., Rosenbaum, J.L. & Witman, G.B. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr. Biol. 12, R378–R380 (2002).

    Article  CAS  Google Scholar 

  17. Yoder, B.K., Hou, X. & Guay-Woodford, L.M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 13, 2508–2516 (2002).

    Article  CAS  Google Scholar 

  18. Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  CAS  Google Scholar 

  19. Ward, C.J. et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum. Mol. Genet. 12, 2703–2710 (2003).

    Article  CAS  Google Scholar 

  20. Gallagher, A.R. et al. Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1. Am. J. Pathol. 172, 417–429 (2008).

    Article  CAS  Google Scholar 

  21. Wang, S., Zhang, J., Nauli, S.M., Starremans, P. & Zhou, J. Fibrocystin is associated with polycystin-2 and regulates intracellular calcium. J. Am. Soc. Nephrol. 15, 12A (2004).

    Article  Google Scholar 

  22. Smith, U.M. et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38, 191–196 (2006).

    Article  CAS  Google Scholar 

  23. Sharma, N., Berbari, N.F. & Yoder, B.K. Ciliary dysfunction in developmental abnormalities and diseases. Curr. Top. Dev. Biol. 85, 371–427 (2008).

    Article  CAS  Google Scholar 

  24. Qian, F. et al. Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proc. Natl. Acad. Sci. USA 99, 16981–16986 (2002).

    Article  CAS  Google Scholar 

  25. Kaimori, J.Y. et al. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum. Mol. Genet. 16, 942–956 (2007).

    Article  CAS  Google Scholar 

  26. Menezes, L.F. & Germino, G.G. Polycystic kidney disease, cilia, and planar polarity. Methods Cell Biol. 94, 273–297 (2009).

    Article  CAS  Google Scholar 

  27. Qian, F., Watnick, T.J., Onuchic, L.F. & Germino, G.G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87, 979–987 (1996).

    Article  CAS  Google Scholar 

  28. Watnick, T.J. et al. Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. Mol. Cell 2, 247–251 (1998).

    Article  CAS  Google Scholar 

  29. Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

    Article  CAS  Google Scholar 

  30. Piontek, K., Menezes, L.F., Garcia-Gonzalez, M.A., Huso, D.L. & Germino, G.G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).

    Article  CAS  Google Scholar 

  31. Spirli, C. et al. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 138, 360–371 (2010).

    Article  CAS  Google Scholar 

  32. Van Keimpema, L. et al. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 31, 92–98 (2011).

    Article  Google Scholar 

  33. Shao, X., Somlo, S. & Igarashi, P. Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. J. Am. Soc. Nephrol. 13, 1837–1846 (2002).

    Article  CAS  Google Scholar 

  34. Shibazaki, S. et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum. Mol. Genet. 17, 1505–1516 (2008).

    Article  CAS  Google Scholar 

  35. Cao, Y. et al. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc. Natl. Acad. Sci. USA 106, 21819–21824 (2009).

    Article  CAS  Google Scholar 

  36. Geng, L. et al. Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2. Proc. Natl. Acad. Sci. USA 105, 15920–15925 (2008).

    Article  CAS  Google Scholar 

  37. Gao, H. et al. PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Hum. Mol. Genet. 19, 16–24 (2010).

    Article  CAS  Google Scholar 

  38. Hanaoka, K. et al. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 408, 990–994 (2000).

    Article  CAS  Google Scholar 

  39. Yu, Y. et al. Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc. Natl. Acad. Sci. USA 106, 11558–11563 (2009).

    Article  CAS  Google Scholar 

  40. Wodarczyk, C. et al. A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE 4, e7137 (2009).

    Article  Google Scholar 

  41. Wu, G. et al. Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum. Mol. Genet. 11, 1845–1854 (2002).

    Article  CAS  Google Scholar 

  42. Nishio, S. et al. Loss of oriented cell division does not initiate cyst formation. J. Am. Soc. Nephrol. 21, 295–302 (2010).

    Article  CAS  Google Scholar 

  43. Garcia-Gonzalez, M.A. et al. Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum. Mol. Genet. 16, 1940–1950 (2007).

    Article  CAS  Google Scholar 

  44. Vembar, S.S. & Brodsky, J.L. One step at a time: endoplasmic reticulum-associated degradation. Nat. Rev. Mol. Cell Biol. 9, 944–957 (2008).

    Article  CAS  Google Scholar 

  45. Pei, Y. et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am. J. Hum. Genet. 68, 355–363 (2001).

    Article  CAS  Google Scholar 

  46. Jiang, S.T. et al. Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am. J. Pathol. 168, 205–220 (2006).

    Article  CAS  Google Scholar 

  47. Lantinga-van Leeuwen, I.S. et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum. Mol. Genet. 13, 3069–3077 (2004).

    Article  CAS  Google Scholar 

  48. Rossetti, S. et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 75, 848–855 (2009).

    Article  CAS  Google Scholar 

  49. Lalioti, M. & Heath, J. A new method for generating point mutations in bacterial artificial chromosomes by homologous recombination in Escherichia coli. Nucleic Acids Res. 29, E14 (2001).

    Article  CAS  Google Scholar 

  50. Wu, G. et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat. Genet. 24, 75–78 (2000).

    Article  CAS  Google Scholar 

  51. Guo, C., Yang, W. & Lobe, C.G. A Cre recombinase transgene with mosaic, widespread tamoxifen-inducible action. Genesis 32, 8–18 (2002).

    Article  CAS  Google Scholar 

  52. Patel, V. et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet. 17, 1578–1590 (2008).

    Article  CAS  Google Scholar 

  53. Cai, Y. et al. Identification and characterization of polycystin-2, the PKD2 gene product. J. Biol. Chem. 274, 28557–28565 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

Carfilzomib was a kind gift from Proteolix, Inc. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)/ US National Institutes of Health (NIH) (R01DK51041 and R01DK54053 to S.S. and F31DK083904 to S.V.F.) and a grant from the Mizutani Foundation for Glycoscience (S.S.). We are grateful for support from the Nephrology Training Grant (T32DK007276) to S.V.F. and the Joseph LeRoy and Ann C. Warner Fund (S.S.). The authors are members of the Yale PKD Center (P50DK57328). We are grateful for Core services from the Yale O'Brien Kidney Center (P30DK079310).

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Author notes

  1. Xin Tian and Anna-Rachel Gallagher: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Sorin V Fedeles, Xin Tian, Anna-Rachel Gallagher, Michihiro Mitobe, Saori Nishio, Seung Hun Lee, Yiqiang Cai, Lin Geng & Stefan Somlo

  2. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Sorin V Fedeles & Stefan Somlo

  3. Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut, USA

    Craig M Crews

  4. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

    Craig M Crews

  5. Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut, USA

    Craig M Crews

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Contributions

S.V.F. co-designed the study, performed the experiments and co-wrote the manuscript. X.T. and M.M. generated the mouse models. A.-R.G. performed experiments, participated in the experimental design and assisted in manuscript preparation. S.N., S.H.L., Y.C. and L.G. carried out experiments. C.M.C. participated in the proteasome inhibitor studies. S.S. came up with the study design and co-wrote the manuscript.

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Correspondence to Stefan Somlo.

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Fedeles, S., Tian, X., Gallagher, AR. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet 43, 639–647 (2011). https://doi.org/10.1038/ng.860

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