| 19933270 |
Banerjee S, Zmijewski JW, Lorne E, Liu G, Sha Y, Abraham E: Modulation of SCF beta-TrCP-dependent I kappaB alpha ubiquitination by hydrogen peroxide. J Biol Chem. 2010 Jan 22;285(4):2665-75. Epub 2009 Nov 20.
Reactive oxygen species are known to participate in the regulation of intracellular signaling pathways, including activation of NF-kappaB. Recent studies have indicated that increases in intracellular concentrations of hydrogen peroxide (H (2) O (2)) have anti-inflammatory effects in neutrophils, including inhibition of the degradation of I kappaB alpha after TLR4 engagement. In the present experiments, we found that culture of lipopolysaccharide-stimulated neutrophils and HEK 293 cells with H (2) O (2) resulted in diminished ubiquitination of I kappaB alpha and decreased SCF (beta-TrCP) ubiquitin ligase activity. Exposure of neutrophils or HEK 293 cells to H (2) O (2) was associated with reduced binding between phosphorylated I kappaB alpha and SCF (beta-TrCP) but no change in the composition of the SCF (beta-TrCP) complex. Lipopolysaccharide-induced SCF (beta-TrCP) ubiquitin ligase activity as well as binding of beta-TrCP to phosphorylated I kappaB alpha was decreased in the lungs of acatalasemic mice and mice treated with the catalase inhibitor aminotriazole, situations in which intracellular concentrations of H (2) O (2) are increased. Exposure to H (2) O (2) resulted in oxidative modification of cysteine residues in beta-TrCP. Cysteine 308 in Blade 1 of the beta-TrCP beta-propeller region was found to be required for maximal binding between beta-TrCP and phosphorylated I kappaB alpha. These findings suggest that the anti-inflammatory effects of H (2) O (2) may result from its ability to decrease ubiquitination as well as subsequent degradation of I kappaB alpha through inhibiting the association between I kappaB alpha and SCF (beta-TrCP). |
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