Translational up-regulation of polycystic kidney disease protein PKD2 by endoplasmic reticulum stress

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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
08:46

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

Published on: September 1, 2015

Jungwoo Yang1, Wang Zheng, Qian Wang

  • 12Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, 7-29 Medical Sciences Bldg., Edmonton, AB T6G 2H7, Canada. xzchen@ualberta.ca.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 30, 2013
PubMed

Insights

Endoplasmic reticulum stress up-regulates polycystic kidney disease 2 (PKD2) protein by enhancing its translation. This occurs via phosphorylated eukaryotic initiation factor 2 alpha (P-eIF2α), which bypasses an inhibitory sequence in the PKD2 mRNA.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) involves cyst formation and is linked to mutations in PKD1 or PKD2.
  • Strict regulation of PKD1/PKD2 expression is crucial for ADPKD pathogenesis, but regulatory mechanisms are poorly understood.
  • Endoplasmic reticulum (ER) stress is implicated in various diseases and has been linked to PKD2 regulation.

Purpose of the Study:

  • To investigate the regulatory mechanisms of PKD2 expression, particularly in response to ER stress.
  • To elucidate the role of phosphorylated eukaryotic initiation factor 2 alpha (P-eIF2α) in PKD2 regulation.
  • To identify the specific sequence elements in PKD2 mRNA responsible for translational control.

Main Methods:

  • Utilized mammalian cell lines to study PKD2 protein expression under various stress conditions.
  • Employed overexpression of P-eIF2α and phosphatase inhibition to assess its effect on PKD2 levels.
  • Performed PCR and polysome-binding assays to analyze PKD2 mRNA levels and translation.
  • Conducted mutation analysis of the 5'-untranslated region of PKD2 mRNA.

Main Results:

  • ER stress and conditions increasing P-eIF2α led to increased PKD2 protein expression.
  • ER stress did not alter PKD2 mRNA levels but enhanced its ribosome binding, indicating translational control.
  • An upstream open reading frame (uORF) in the 5'-untranslated region of PKD2 mRNA was identified as a translational repressor.
  • P-eIF2α mediated the translational upregulation of PKD2 by bypassing the inhibitory uORF.

Conclusions:

  • ER stress translationally up-regulates PKD2 protein levels through the P-eIF2α pathway.
  • The findings reveal a novel mechanism of translational control for PKD2 involving an uORF and ER stress response.
  • This study provides insights into ADPKD pathogenesis and potential therapeutic targets related to ER stress and PKD2 regulation.

Keywords:
ADPKDP-eIF2αuORF

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