Kidney Week

Abstract: FR-PO979

The C-Term of Human Fibrocystin Regulates STAT3-Dependent Transcription

Session Information

• PKD Cellular Pathogenesis, ARPKD, ADTKD, Ciliopathies
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Mandel, Amrei Maxi, University of Cologne, Cologne, Germany

Amrei Maxi Mandel,

• Dafinger, Claudia, University of Cologne, Cologne, Germany

Claudia Dafinger,

• Benzing, Thomas, University of Cologne, Cologne, Germany

Thomas Benzing,

• Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States

Thomas Weimbs,

• Schermer, Bernhard, University of Cologne, Cologne, Germany

Bernhard Schermer,

• Liebau, Max, University of Cologne, Cologne, Germany

Max Liebau,

Background

Autosomal recessive polycystic kidney disease (ARPKD) is the rare but severe form of PKD characterized by early fibrocystic renal alterations and congenital hepatic fibrosis. The disease is mainly caused by mutations in PKHD1, encoding the 4,074aa transmembrane protein Fibrocystin (FC). The molecular mechanisms leading to ARPKD and Fibrocystin’s cellular function are poorly understood. Experimental and clinical data suggest that there may be partial overlap with pathomechanisms of autosomal dominant PKD.

Methods

We evaluated effects of the C-term of human FC on STAT3-dependent transcription and the SRC-STAT3 axis by applying standard techniques such as immunoprecipitation, immunochemistry and luciferase reporter assays.

Results

We identify a link of human FC to the regulation of STAT3-dependent transcription with activation of factor STAT3 in cyst-lining epithelial cells of ARPKD patient kidneys. Strikingly, a C-terminal truncation of FC negatively regulates SRC- and JAK2-dependent STAT3 activity and can be found in a common protein complex with SRC and JAK2. C-terminal FC also modulates SRC-dependent STAT3-activation after SRC-activation by forskolin-induced increased intracellular levels of cAMP. Mutation analyses point to a role of C-term FC in the activation of SRC.

Conclusion

This data is in accordance with recent observations that showed a beneficial effect of both SRC and STAT3 inhibitors in orthologous and non-orthologous rodent models of PKD. We present insights into potential molecular mechanisms by providing evidence for a regulation of the SRC-STAT3-axis by human C-terminal FC.

Funding

• Government Support - Non-U.S.