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 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

作者机构：State Key Laboratory of Quality Research in Chinese Medicine/Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao SAR 999078China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China Guangdong Provincial Key Laboratory of New Drug Screening/Laboratory of Anti-inflammatory and Immunomodulatory PharmacologySchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious DiseaseMacao University of Science and TechnologyMacao SAR 999078China Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of ChinaMacao University of Science and TechnologyMacao SAR 999078China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第2期

页      面：651-664,F0004页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：Department of Science and Technology of Guangdong Province for financially supporting Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease funded by The Science and Technology Development Fund,Macao SAR(project code 0017/2018/A1,0002/2019/APD China)。 

主　　题：IKKβ Homeostasis Kinase domain AMPK Inflammation IκBα Anti-inflammatory drug Phosphorylation 

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 IKKβhas been a therapeutic strategy for inflammatory and autoimmune diseases.Here we report that IKKβis constitutively activated in healthy donors and healthy Ikkβ^(C46A)(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation.These indicate that IKKβactivation probably plays homeostatic role instead of causing inflammation.Compared to IkkβWTlittermates,lipopolysaccharides(LPS)could induce high mortality rate in Ikkβ^(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5’adenosine monophosphate-activated protein kinase(p-AMPK)expression.We then demonstrated that IKKβkinase domain(KD)phosphorylates AMPKa1 via interacting with residues Thr183,Ser184,and Thr388,while IKKβhelix-loop-helix motifs is essential to phosphorylate IκBαaccording to the previous reports.Kinase assay further demonstrated that IKKβsimultaneously catalyzes phosphorylation of AMPK and IκBαto mediate homeostasis.Accordingly,activation of AMPK rather than inhibition of IKKβcould substantially rescue LPS-induced mortality in Ikkβ^(C46A) mice by rebuilding the homeostasis.We conclude that IKKβactivates AMPK to restrict inflammation and IKKβmediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.