SON DNA-binding protein mediates macrophage autophagy and responses to intracellular infection

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Intracellular pathogens disrupt host cellular defense and metabolic pathways.
• Macrophages are key immune cells involved in combating intracellular infections.

Purpose of the Study:

• To identify host factors regulating macrophage responses to intracellular pathogens.
• To investigate the role of SON DNA-binding protein in macrophage defense mechanisms.

Main Methods:

• Utilized RNA interference (RNAi) to knock down SON expression in human macrophages.
• Infected macrophages with Francisella tularensis and stimulated inflammasomes.
• Assessed macrophage survival, autophagy, interferon response factor 3 (IRF3) expression, type I interferon response, and inflammasome readouts.
• Analyzed gene expression and splicing, focusing on GBF1.
• Inhibited GBF1 chemically.

Main Results:

• SON knockdown significantly increased human macrophage survival following Francisella tularensis infection and inflammasome stimulation.
• SON is essential for macrophage autophagy, IRF3 expression, type I interferon response, and inflammasome activation.
• SON regulates gene and stimulus-specific inflammatory gene expression.
• SON is required for the accurate splicing and expression of GBF1, a regulator of cis-Golgi structure.
• Chemical inhibition of GBF1 mimicked the effects of SON knockdown.

Conclusions:

• SON is a central determinant of macrophage activities during intracellular pathogen infection.
• SON regulates macrophage defense pathways, including autophagy and interferon responses, partly through controlling Golgi-associated processes via GBF1.