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Repression of classical nuclear export by S-nitrosylation of CRM1

Peng Wang1, Guang-Hui Liu, Kaiyuan Wu

  • 1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 PR China.

Journal of Cell Science
|October 9, 2009
PubMed

Insights

Nitric oxide (NO) modifies chromosomal region maintenance 1 (CRM1) through S-nitrosylation, inhibiting nuclear export. This NO-induced CRM1 inactivation promotes nuclear accumulation of Nrf2, activating protective genes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Chromosomal region maintenance 1 (CRM1) is the primary receptor for classical nuclear protein export.
  • Regulation of CRM1 itself remains largely uncharacterized, particularly under conditions of nitrosative stress.

Purpose of the Study:

  • To investigate the regulatory mechanisms of CRM1.
  • To determine the effect of nitric oxide (NO) on CRM1 function and its downstream consequences.

Main Methods:

  • Exposure of cells to endogenous or exogenous NO.
  • Mass spectrometry analysis to identify S-nitrosylation sites on CRM1.
  • Site-directed mutagenesis to create S-nitrosylation-resistant CRM1 mutants.
  • Assessment of CRM1-NES interaction and nuclear export activity.
  • Analysis of Nrf2 nuclear accumulation and transcriptional activity.

Main Results:

  • Cellular CRM1 undergoes S-nitrosylation upon exposure to NO.
  • S-nitrosylation at specific cysteine residues abrogates CRM1 interaction with nuclear export signals (NESs).
  • This modification represses classical protein export and leads to nuclear accumulation of Nrf2.
  • Overexpression of S-nitrosylation-resistant CRM1 mutants rescues NO-induced export repression.

Conclusions:

  • CRM1 is negatively regulated by S-nitrosylation under nitrosative stress.
  • NO-mediated inactivation of CRM1 enhances the nuclear translocation and activity of Nrf2.
  • This pathway likely contributes to a cytoprotective transcriptional response against nitrosative stress.

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