Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response

Kate Petersen Shay, Alexander J. Michels, Wenge Li, Ah Ng Tony Kong, Tory M. Hagen

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24. h following treatment with the dithiol micronutrient (R)-α-lipoic acid (LA; 50 μM), or vehicle. LA caused a ≥ 2.5-fold increase in nuclear Nrf2 within 1 h. However, pretreating cells with cycloheximide (50 μg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4. h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P < 0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli.

Original languageEnglish (US)
Pages (from-to)1102-1109
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1823
Issue number6
DOIs
StatePublished - Jun 1 2012

Keywords

  • Cap-independent translation
  • Cellular stress
  • Lipoic acid
  • Mammalian target of rapamycin (mTOR)
  • Nrf2
  • Protein homeostasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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