Mutation of cysteine 46 in IKK-beta increases inflammatory responses.

ABSTRACT: Activation of I?B kinase ? (IKK-?) and nuclear factor (NF)-?B signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-?-NF-?B signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-?B signaling by binding to specific cysteine residues on IKK-?. However, mutations in IKK-? have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-? inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-? kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-? C46A transgenic mouse model. We show that a novel IKK-? inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-? C46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-?.

SUBMITTER: Li T 

PROVIDER: S-EPMC4741641 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature