IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα

• 作者: Juan Liu Yuxin Zhuang Jianlin Wu Qiang Wu Meixian Liu Yue Zhao Zhongqiu Liu Caiyan Wang Linlin Lu Yingjiao Meng Kawai Lei Xiaojuan Li Qibiao Wu Elaine Lai-Han Leung Zhengyang Guo Liang Liu Ting Li
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: Original articles
• 页码范围: 651-664
• 页数: 14页
• 语种: 英文

摘要

Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases.Here we report that IKKβ is constitutively activated in healthy donors and healthy IkkβC46A(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation.These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation.Compared to IkkβWT littermates,lipopolysaccharides(LPS)could induce high mortality rate in IkkβC46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5'adenosine monophosphate-activated pro-tein kinase(p-AMPK)expression.We then demonstrated that IKKβ kinase domain(KD)phosphorylates AMPKαl via interacting with residues Thr183,Ser184,and Thr388,while 1KKβ helix-loop-helix mo-tifs is essential to phosphorylate IκBα according to the previous reports.Kinase assay further demon-strated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis.Accordingly,activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in IkkβC46A mice by rebuilding the homeostasis.We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competi-tively phosphorylating AMPK and IκBα.