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Published on: January 7, 2019
Munc13-4-STX7 inhibitors impair endosomal TLR activation and systemic inflammation
Jennifer L Johnson1, Elsa Meneses-Salas1, Aparna Shukla1
1Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.
Abstract:
Endosomal function is essential for pattern recognition receptor signaling, through endosomal Toll-like receptor (TLR) sensing of nonself RNA and DNA. The specific interaction of the calcium sensor Munc13-4 with syntaxin 7 (STX7) regulates endosomal flux and Munc13-4 depletion decreases the systemic inflammatory response to unmethylated DNA. Using high-throughput screening and orthogonal cell-based validation, we identified small-molecule inhibitors of the Munc13-4-STX7 interaction, ENDOtollins (ENDOs). ENDOs inhibit extracellular signal-regulated kinase signaling in neutrophils and interferon (IFN) regulatory factor signaling in plasmacytoid dendritic cells (DCs) in response to endosomal TLR ligands but not to plasma membrane agonists, highlighting specificity for the endocytic pathway. Mechanistically, ENDOs inhibit endolysosomal flux and decrease endolysosomal cargo degradation. Chemical optimization identified ENDO12 as the most potent inhibitor. ENDO12 inhibited primary DC responses to TLR3, TLR7 and TLR9 and reduced CpG-induced systemic inflammation, manifested as decreased levels of the proinflammatory mediators myeloperoxidase, interleukin 6 and IFNγ. Our findings have significant implications for immunodeficiency, inflammation and innate immunity.
Insights
Researchers discovered small molecules called ENDOtollins (ENDOs) that block a key protein interaction in endosomes. These ENDOs reduce inflammatory responses by targeting endosomal Toll-like receptors (TLRs), offering potential for treating inflammatory diseases.
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.
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