Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKβ

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase implicated in neurogenesis and cancer.
• Emerging evidence suggests DCLK1's involvement in inflammatory processes, particularly in colitis models.
• The precise cellular mechanisms and molecular targets of DCLK1 in inflammation remain largely uncharacterized.

Purpose of the Study:

• To elucidate the role of DCLK1 in regulating inflammatory responses.
• To identify the specific molecular pathways and substrates through which DCLK1 exerts its inflammatory effects.
• To evaluate the therapeutic potential of targeting DCLK1 for inflammatory diseases.

Main Methods:

• Utilized lipopolysaccharide (LPS)-stimulated macrophages as a model system.
• Employed macrophage-based and cell-free assays to investigate DCLK1-protein interactions.
• Generated myeloid-specific DCLK1 knockout mice and used pharmacological DCLK1 inhibitors.
• Assessed NF-κB pathway activation, cytokine production, and outcomes in acute lung injury and sepsis models.

Main Results:

• Discovered direct binding of DCLK1 to inhibitor of κB kinase β (IKKβ).
• Demonstrated that DCLK1 induces IKKβ phosphorylation at Ser177/181, activating the nuclear factor-κB (NF-κB) pathway.
• Showed that DCLK1 deficiency or inhibition abrogates LPS-induced NF-κB activation and pro-inflammatory cytokine release in macrophages.
• Confirmed protection against LPS-induced acute lung injury and septic death in mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment.

Conclusions:

• Reported a novel function of macrophage DCLK1 as a direct regulator of IKKβ in inflammatory signaling.
• Established the DCLK1-IKKβ-NF-κB axis as a critical component of the inflammatory response.
• Proposed DCLK1 as a promising therapeutic target for managing inflammatory diseases.