Glutathionylation regulates IκB

Although there has been considerable interest in the regulation of NFκB activation by glutathionylation, the possibility of IκB as a target for glutathionylation has not been investigated. We now report that Cys189 of IκBα is a target for S-glutathionylation. This modification is reversed by thiols such as dithiothreitol and GSH. The glutathionylated IκBα appears to be significantly less susceptible than is native protein to phosphorylation by IκB kinase and casein kinase II, as well as to in vitro ubiquitination. This finding suggests that glutathionylation plays a regulatory role, presumably through structural alterations. HeLa cells treated with oxidant inducing GSH oxidation such as diamide showed the accumulation of glutathionylated IκBα. This mechanism suggests an alternative modification to the redox regulation of cysteine in IκBα and a possible mechanism in the regulation of NFκB activation.