TLR-induced STK25 activation promotes IRF5-mediated inflammation

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• Interferon regulatory factor 5 (IRF5) is crucial for inflammatory responses via MyD88-dependent Toll-like receptors (TLRs).
• IRF5 dysregulation is linked to autoimmune diseases like systemic lupus erythematosus.
• Modulators of TLR-induced IRF5 post-translational modifications remain largely unknown.

Purpose of the Study:

• Identify novel kinases regulating Toll-like receptor (TLR)-Myeloid differentiation primary response 88 (MyD88)-interferon regulatory factor 5 (IRF5) signaling.
• Investigate the role of serine/threonine protein kinase 25 (STK25) in IRF5-mediated inflammatory pathways.

Main Methods:

• Performed a kinome-wide siRNA screen in human THP-1 monocytic cells.
• Utilized STK25-deficient primary immune cells for validation.
• Assessed IRF5 phosphorylation, nuclear translocation, and cytokine production.

Main Results:

• Identified STK25 as a positive regulator of pro-inflammatory cytokine production through IRF5 phosphorylation at Thr265.
• STK25 autophosphorylation was observed upon TLR stimulation.
• STK25 deficiency significantly reduced R848-induced IRF5 nuclear translocation and cytokine production.
• Elevated STK25 autophosphorylation was found in immune cells from systemic lupus erythematosus patients.

Conclusions:

• STK25 acts as a novel kinase in TLR signaling by modulating IRF5 activation.
• STK25 plays a significant role in TLR7/8-mediated inflammatory responses.
• Aberrant STK25 activity may contribute to the pathogenesis of systemic lupus erythematosus.