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IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
- Source :
- Acta Pharmaceutica Sinica B; Feb2022, Vol. 12 Issue 2, p651-664, 14p
- Publication Year :
- 2022
-
Abstract
- Inhibitor of nuclear factor kappa-B kinase subunit beta (IKK β) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (I κ B α) and then activate nuclear factor kappa-B (NF- κ B). Inhibition of IKK β has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKK β is constitutively activated in healthy donors and healthy Ikkβ <superscript> C46A </superscript> (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKK β –I κ B α –NF- κ B signaling activation. These indicate that IKK β activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ <superscript> WT </superscript> littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ <superscript> C46A </superscript> mice which is correlated to breaking the homeostasis by intensively activating p-I κ B α –NF- κ B signaling and inhibiting phosphorylation of 5ʹ adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKK β kinase domain (KD) phosphorylates AMPK α 1 via interacting with residues Thr183, Ser184, and Thr388, while IKK β helix–loop–helix motifs is essential to phosphorylate I κ B α according to the previous reports. Kinase assay further demonstrated that IKK β simultaneously catalyzes phosphorylation of AMPK and I κ B α to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKK β could substantially rescue LPS-induced mortality in Ikkβ <superscript> C46A </superscript> mice by rebuilding the homeostasis. We conclude that IKK β activates AMPK to restrict inflammation and IKK β mediates homeostatic function in inflammation via competitively phosphorylating AMPK and I κ B α. The dual and opposite role of inhibitor of nuclear factor kappa-B kinase subunit beta (IKK β) restricts and induces inflammation by phosphorylating 5ʹ adenosine monophosphate-activated protein kinase (AMPK) and inhibitor of nuclear factor kappa-B (I κ B α). [Display omitted] [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 22113835
- Volume :
- 12
- Issue :
- 2
- Database :
- Supplemental Index
- Journal :
- Acta Pharmaceutica Sinica B
- Publication Type :
- Academic Journal
- Accession number :
- 155363601
- Full Text :
- https://doi.org/10.1016/j.apsb.2021.09.012