Mutation of cysteine 46 in IKK-beta increases inflammatory responses
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Ting Li1,*, Vincent Kam Wai Wong1,*, Zhi Hong Jiang1, Shui Ping Jiang1, Yan Liu2, Ting Yu Wang2, Xiao Jun Yao1, Xiao Hui Su1, Feng Gen Yan1, Juan Liu1, Elaine Lai-Han Leung1, Xiao Qin Yi2, Yuen Fan Wong2, Hua Zhou1 and Liang Liu1
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
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
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.
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