Munc13-4-STX7 inhibitors impair endosomal TLR activation and systemic inflammation

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Endosomal Toll-like receptors (TLRs) are crucial for detecting foreign RNA and DNA, initiating innate immune responses.
• The Munc13-4 and syntaxin 7 (STX7) interaction regulates endosomal flux, impacting inflammatory signaling.

Purpose of the Study:

• To identify small molecules that inhibit the Munc13-4-STX7 interaction.
• To investigate the effects of these inhibitors on endosomal TLR signaling and inflammatory responses.

Main Methods:

• High-throughput screening and cell-based assays to identify Munc13-4-STX7 inhibitors (ENDOtollins).
• Assessment of ENDOtollins' effects on signaling pathways (ERK, IRF) in neutrophils and dendritic cells (DCs).
• Evaluation of ENDO12's impact on endolysosomal flux, cargo degradation, and systemic inflammation markers.

Main Results:

• Small-molecule inhibitors, ENDOtollins (ENDOs), targeting the Munc13-4-STX7 interaction were identified.
• ENDOs specifically inhibited endosomal TLR signaling, not plasma membrane TLR signaling.
• The optimized inhibitor ENDO12 reduced DC responses to TLR3, TLR7, and TLR9, and decreased systemic inflammation markers.

Conclusions:

• ENDOtollins are potent inhibitors of endosomal TLR signaling by disrupting endosomal flux.
• Targeting the Munc13-4-STX7 interaction offers a novel therapeutic strategy for inflammatory and immunodeficiency disorders.