Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Gold compound auranofin inhibits $I{\kappa}B$ kinase (IKK) by modifying Cys-179 of $IKK{\beta}$ subunit

Jeon, Kye-Im;Byun, Mi-Sun;Jue, Dae-Myung

  • Published : 2003.04.30
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Abstract

Antirheumatic gold compounds have been shown to inhibit NF-${\kappa}$B activation by blocking I${\kappa}$B kinase (IKK) activity. To examine the possible inhibitory mechanism of gold compounds, we expressed wild type and mutant forms of IKK${\alpha}$ and ${\beta}$ subunits in COS-7 cells and determined the effect of gold on the activity of these enzymes both in vivo and in vitro. Substitution of Cys-179 of IKK${\beta}$ with alanine (C179A) rendered the enzyme to become resistant to inhibition by a gold compound auranofin, however, similar protective effect was not observed with an equivalent level of IKK${\alpha}$ (C178A) mutant expressed in the cells. Auranofin inhibited constitutively active IKK${\alpha}$ and ${\beta}$ and variants; IKK${\alpha}$ (S176E, S180E) or IKK${\beta}$ (S177E, S181E), suggesting that gold directly cause inhibition of activated enzyme. The different inhibitory effect of auranofin on IKK${\alpha}$ (C178A) and IKK${\beta}$ (C179A) mutants indicates that gold could inhibit the two subunits of IKK in a different mode, and the inhibition of NF-${\kappa}$B and IKK activation induced by inflammatory signals in gold-treated cells appears through its interaction with Cys-179 of IKK${\beta}$.

Keywords

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