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

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

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

Author: Juan LIU ¹ ; Yuxin ZHUANG ¹ ; Jianlin WU ¹ ; Qiang WU ¹ ; Meixian LIU ¹ ; Yue ZHAO ¹ ; Zhongqiu LIU ² ; Caiyan WANG ² ; Linlin LU ² ; Yingjiao MENG ¹ ; Kawai LEI ¹ ; Xiaojuan LI ³ ; Qibiao WU ¹ ; Elaine Lai-Han LEUNG ¹ ; Zhengyang GUO ¹ ; Liang LIU ¹ ; Ting LI ¹
Author Information

1. State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau SAR 999078, China.
2. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
3. Guangdong Provincial Key Laboratory of New Drug Screening/ Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Publication Type:Journal Article
Keywords: AMPK; Anti-inflammatory drug; Homeostasis; IKKβ; Inflammation; IκBα; Kinase domain; Phosphorylation
From: Acta Pharmaceutica Sinica B 2022;12(2):651-664
CountryChina
Language:English
Abstract: 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 Ikkβ ^C46A (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 Ikkβ ^WT littermates, 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 IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated 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 Ikkβ ^C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.