Tyrosine nitration of IκBα: A novel mechanism for NF-κB activation

Vasily A. Yakovlev, Igor J. Barani, Christopher S. Rabender, Stephen Matthew Black, J. Kevin Leach, Paul R. Graves, Glen E. Kellogg, Ross B. Mikkelsen

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

The NF-κB family of transcription factors is an important component of stress-activated cytoprotective signal transduction pathways. Previous studies demonstrated that some activation mechanisms require phosphorylation, ubiquitination, and degradation of the inhibitor protein, IκBα. Herein, it is demonstrated that ionizing radiation in the therapeutic dose range stimulates NF-κB activity by a mechanism in which IκBα tyrosine 181 is nitrated as a consequence of constitutive NO synthase activation, leading to dissociation of intact IκBα from NF-κB. This mechanism does not appear to require IκBα kinase-dependent phosphorylation or proteolytic degradation of IκBα. Tyrosine 181 is involved in several noncovalent interactions with the p50 subunit of NF-κB stabilizing the IκBα-NF-κB complex. Evaluation of hydropathic interactions of the IκBα-p50 complex on the basis of the crystal structure of the complex is consistent with nitration disrupting these interactions and dissociating the IκBα-NF-κB complex. Tyrosine nitration is not commonly studied in the context of signal transduction. However, these results indicate that tyrosine nitration is an important post-translational regulatory modification for NF-κB activation and possibly for other signaling molecules modulated by mild and transient oxidative and nitrosative stresses.

Original languageEnglish (US)
Pages (from-to)11671-11683
Number of pages13
JournalBiochemistry
Volume46
Issue number42
DOIs
StatePublished - Oct 23 2007

ASJC Scopus subject areas

  • Biochemistry

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    Yakovlev, V. A., Barani, I. J., Rabender, C. S., Black, S. M., Leach, J. K., Graves, P. R., Kellogg, G. E., & Mikkelsen, R. B. (2007). Tyrosine nitration of IκBα: A novel mechanism for NF-κB activation. Biochemistry, 46(42), 11671-11683. https://doi.org/10.1021/bi701107z