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The karyopherin chromosomal region maintenance 1 (CRM1) is the major receptor for classical nuclear protein export. However, little is known about the regulation of CRM1 itself. Here, we report that cellular CRM1 became S-nitrosylated after extensive exposure to endogenous or exogenous nitric oxide (NO). This abrogated the interaction of CRM1 with nuclear export signals (NESs) and repressed classical protein export. Analysis by mass spectrometry and involving the use of S-nitrosylation mimetic mutations indicated that modification at either of two specific cysteines of CRM1 was sufficient to abolish the CRM1-NES association. Moreover, ectopic overexpression of the corresponding S-nitrosylation-resistant CRM1 mutants rescued NO-induced repression of nuclear export. We also found that inactivation of CRM1 by NO facilitated the nuclear accumulation of the antioxidant response transcription factor Nrf2 and transcriptional activation of Nrf2-controlled genes. Together, these data demonstrate that CRM1 is negatively regulated by S-nitrosylation under nitrosative stress. We speculate that this is important for promoting a cytoprotective transcriptional response to nitrosative stress.


  • Supplementary material available online at

  • We gratefully acknowledge Beric R. Henderson (Westmead Institute for Cancer Research, The University of Sydney, Westmead, Australia), Silvia Smaldone (Child Health Institute of New Jersey, Robert W. Johnson Medical School, New Brunswick, NJ), Shirley Knauer (Institute for Biomedical Research, Frankfurt, Germany) and Regina Brigelius-Flohe (German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany) for providing plasmids. We also thank Xudong Zhao (Institute of Biophysics, Chinese Academy of Sciences, Beijing, China) for technical assistance. The work was supported by grants from the National Basic Research Program of China (2006CB911001, 2005CB522804; to C.C.), the National Natural Science Foundation of China (30270352, 30770512; to C.C.) and the US National Institutes of Health (P50 GM082545; to L.G.). Deposited in PMC for release after 12 months.

  • * These authors contributed equally to this work

  • Current address: Gene expression laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA

  • Accepted August 16, 2009.
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