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Phosphorylated PKR contributes the induction of GRP94 under ER stress

Mototsugu Ito1, Reiko Onuki, Yoshio Bando

  • 1Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 13-0033, Japan.

Biochemical and Biophysical Research Communications
|July 7, 2007
PubMed

Insights

Phosphorylated double-stranded RNA-dependent protein kinase (PKR) contributes to the induction of glucose-regulated protein 94 (GRP94) during ER stress. A novel mechanism, independent of ERSE-dependent transcription, is involved in GRP94 induction.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphorylated double-stranded RNA-dependent protein kinase (PKR) is implicated in ER stress-induced cell death.
  • The precise molecular mechanism of PKR's action during ER stress remains unclear.

Purpose of the Study:

  • To elucidate the role of PKR in ER stress response.
  • To investigate the mechanism of GRP94 induction under ER stress.

Main Methods:

  • Utilized PKR inhibitor with ER stress inducers (tunicamycin, thapsigargin, 2-deoxyglucose) in SK-N-SH and HepG2 cells.
  • Assessed protein and mRNA levels of GRP94 and GRP78.
  • Analyzed mRNA levels of spliced X box binding protein 1 (XBP1).
  • Performed reporter gene assays using GRP78 and GRP94 promoters with an ER stress response element (ERSE).

Main Results:

  • PKR inhibition suppressed the induction of GRP94 protein and mRNA, but not GRP78.
  • GRP94 mRNA levels increased, but XBP1 splicing was not significantly affected.
  • PKR inhibitor did not alter the activity of GRP78 and GRP94 promoters via ERSE.

Conclusions:

  • PKR phosphorylation contributes to GRP94 induction during ER stress.
  • A novel mechanism, independent of ERSE-dependent mRNA transcription, mediates GRP94 induction.
  • PKR's role in ER stress involves GRP94 regulation through a non-canonical pathway.

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