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

61 Citations (Scopus)

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

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Nitration
Tyrosine
Chemical activation
Signal transduction
Phosphorylation
Signal Transduction
Degradation
Ubiquitination
Ionizing radiation
Corrosion inhibitors
Post Translational Protein Processing
Ionizing Radiation
Nitric Oxide Synthase
Proteolysis
Dosimetry
Oxidative Stress
Transcription Factors
Phosphotransferases
Crystal structure
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Yakovlev, V. A., Barani, I. J., Rabender, C. S., Black, S. M., Leach, J. K., Graves, P. R., ... 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

Tyrosine nitration of IκBα : A novel mechanism for NF-κB activation. / Yakovlev, Vasily A.; Barani, Igor J.; Rabender, Christopher S.; Black, Stephen Matthew; Leach, J. Kevin; Graves, Paul R.; Kellogg, Glen E.; Mikkelsen, Ross B.

In: Biochemistry, Vol. 46, No. 42, 23.10.2007, p. 11671-11683.

Research output: Contribution to journalArticle

Yakovlev, VA, Barani, IJ, Rabender, CS, Black, SM, Leach, JK, Graves, PR, Kellogg, GE & Mikkelsen, RB 2007, 'Tyrosine nitration of IκBα: A novel mechanism for NF-κB activation', Biochemistry, vol. 46, no. 42, pp. 11671-11683. https://doi.org/10.1021/bi701107z
Yakovlev VA, Barani IJ, Rabender CS, Black SM, Leach JK, Graves PR et al. Tyrosine nitration of IκBα: A novel mechanism for NF-κB activation. Biochemistry. 2007 Oct 23;46(42):11671-11683. https://doi.org/10.1021/bi701107z
Yakovlev, Vasily A. ; Barani, Igor J. ; Rabender, Christopher S. ; Black, Stephen Matthew ; Leach, J. Kevin ; Graves, Paul R. ; Kellogg, Glen E. ; Mikkelsen, Ross B. / Tyrosine nitration of IκBα : A novel mechanism for NF-κB activation. In: Biochemistry. 2007 ; Vol. 46, No. 42. pp. 11671-11683.
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