Mutation of cysteine 46 in IKK-beta increases inflammatory responses

// Ting Li 1,* , Vincent Kam Wai Wong 1,* , Zhi Hong Jiang 1 , Shui Ping Jiang 1 , Yan Liu 2 , Ting Yu Wang 2 , Xiao Jun Yao 1 , Xiao Hui Su 1 , Feng Gen Yan 1 , Juan Liu 1 , Elaine Lai-Han Leung 1 , Xiao Qin Yi 2 , Yuen Fan Wong 2 , Hua Zhou 1 and Liang Liu 1 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China 2 Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China * These authors contributed equally to this work Correspondence to: Liang Liu, email: // Hua Zhou, email: // Keywords : cysteine mutation, dihydromyricetin, IKK-β inhibitor, inflammation, NF-κB Received : April 15, 2015 Accepted : August 13, 2015 Published : September 10, 2015 Abstract Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β−NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-β C46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-β 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-β.