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

The NF-kappa B 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, I kappa B alpha. Herein, it is demonstrated that ionizing radiation in the therapeutic dose range stimulates NF-kappa B activity by a mechanism in which I kappa B alpha tyrosine 181 is nitrated as a consequence of constitutive NO center dot synthase activation, leading to dissociation of intact I kappa B alpha from NF-kappa B. This mechanism does not appear to require I kappa B alpha kinase-dependent phosphorylation or proteolytic degradation of I kappa B alpha. Tyrosine 181 is involved in several noncovalent interactions with the p50 subunit of NF-kappa B stabilizing the I kappa B alpha-NF-kappa B complex. Evaluation of hydropathic interactions of the I kappa B alpha-p50 complex on the basis of the crystal structure of the complex is consistent with nitration disrupting these interactions and dissociating the I kappa B alpha-NF-kappa B 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-kappa B activation and possibly for other signaling molecules modulated by mild and transient oxidative and nitrosative stresses.