Repression of classical nuclear export by S-nitrosylation of CRM1.
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.
Wang
Peng
P
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 PR China.
Liu
Guang-Hui
GH
Wu
Kaiyuan
K
Qu
Jing
J
Huang
Bo
B
Zhang
Xu
X
Zhou
Xixi
X
Gerace
Larry
L
Chen
Chang
C
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000097606:Exportin 1 Protein
D028884:Karyopherins; D051267:NF-E2-Related Factor 2; D009569:Nitric Oxide; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D026422:S-Nitrosoglutathione; D000097606:Exportin 1 Protein