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

Biochim Biophys Acta. 2012 Jun;1823(6):1102-9. doi: 10.1016/j.bbamcr.2012.04.002. Epub 2012 Apr 13.


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 24h following treatment with the dithiol micronutrient (R)-α-lipoic acid (LA; 50μM), or vehicle. LA caused a ≥2.5-fold increase in nuclear Nrf2 within 1h. However, pretreating cells with cycloheximide (50μg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4h, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Cell Compartmentation / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Hep G2 Cells
  • Humans
  • Inactivation, Metabolic*
  • NF-E2-Related Factor 2 / biosynthesis*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Biosynthesis / drug effects*
  • RNA Caps / drug effects
  • RNA Caps / metabolism*
  • Sirolimus / pharmacology
  • Stress, Physiological / drug effects*
  • Thioctic Acid / pharmacology*


  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proteasome Inhibitors
  • RNA Caps
  • Thioctic Acid
  • Proteasome Endopeptidase Complex
  • Sirolimus