Tyrosine nitration on p65: A novel mechanism to rapidly inactive nuclear factor-κB

Sung Wook Park, M. D Mostaqul Huq, Xinli Hu, Li-Na Wei

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

NO is an important factor that induces post-translational modifications of proteins by cellular reduction and oxidation mechanism: cysteinyl-nitrosylation or Tyr nitration. Nuclear factor (NF)-κB activity can be rapidly suppressed by sodium nitroprusside, a NO donor. This effect was effectively reversed by peroxynitrite scavenger deferoxamine, suggesting a Tyr nitration-mediated mechanism. Western blot with nitrotyrosine-specific antibody demonstrated that the p65 subunit of NF-κB was predominantly nitrated on Tyr residues. Tyr nitration of p65 induced its dissociation from p50, its association with IκBα, and subsequent sequestration of p65 in the cytoplasm by IκBα-mediated export. Liquid chromatography-coupled nano-electrospray mass spectrometry revealed specific nitration on Tyr-66 and Tyr-152 residues of p65. Mutation studies confirmed that both Tyr-66 and Tyr-152 residues were important for the direct effects of NO on p65, which resulted in more p65 export and inactivation of NF-κB activity. This study identified a novel and efficient pathway where NO rapidly inactivated NF-κB activity by inducing Tyr nitration on p65.

Original languageEnglish (US)
Pages (from-to)300-309
Number of pages10
JournalMolecular and Cellular Proteomics
Volume4
Issue number3
DOIs
StatePublished - Mar 2005

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