IKK beta mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IkB alpha

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKK beta) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (I kappa B alpha) and then activate nuclear factor kappa-B (NF-kappa B). Inhibition of IKK beta has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKK beta is constitutively activated in healthy donors and healthy IkK beta(C46A) (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKK beta-I kappa B alpha-NF-kappa B signaling activation. These indicate that IKK beta activation probably plays homeostatic role instead of causing inflammation. Compared to IkK beta(WT) littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikk/5(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-I kappa B alpha-NF-kappa B signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKK/5 kinase domain (KD) phosphorylates AMPK alpha 1 via interacting with residues Thr183, Ser184, and Thr388, while IKK/5 helix-loop-helix motifs is essential to phosphorylate I kappa B alpha according to the previous reports. Kinase assay further demonstrated that IKK/5 simultaneously catalyzes phosphorylation of AMPK and I kappa B alpha to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKK/5 could substantially rescue LPS-induced mortality in Ikk/5(C46A) mice by rebuilding the homeostasis. We conclude that IKK/5 activates AMPK to restrict inflammation and IKK/5 mediates homeostatic function in inflammation via competitively phosphorylating AMPK and I kappa B alpha. (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).