Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis, and its levels are elevated in various human cancers. Recent studies suggest that DCLK1 may relate to inflammatory responses in the mouse model of colitis. However, cellular pathways engaged by DCLK1, and potential substrates of the kinase remain undefined. To understand how DCLK1 regulates inflammatory responses, we utilized the well-established lipopolysaccharide (LPS)-stimulated macrophages and mouse model. Through a range of macrophage-based and cell-free platforms, we discovered that DCLK1 binds directly with the inhibitor of κB kinase β (IKKβ) and induces IKKβ phosphorylation on Ser177/181 to initiate nuclear factor-κB (NF-κB) pathway. Deficiency in DCLK1, achieved by silencing or through pharmacological inhibition, prevented LPS-induced NF-κB activation and cytokine production in macrophages. We further show that mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment are protected against LPS-induced acute lung injury and septic death. Our studies report a novel functional role of macrophage DCLK1 as a direct IKKβ regulator in inflammatory signaling and suggest targeted therapy against DCLK1 for inflammatory diseases.
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This study was supported by the National Natural Science Foundation of China (81930108 to GL, 82000793 to WL, and 82170373 to YW), Natural Science Foundation of Zhejiang Province (LY22H070004 to WL), and Zhejiang Provincial Key Scientific Project (2021C03041 to GL).
The authors declare no competing interests.
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Luo, W., Jin, Y., Jiang, Y. et al. Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKβ. Cell Death Differ 30, 1184–1197 (2023). https://doi.org/10.1038/s41418-023-01147-8