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SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions
Emil Carlsson1, Jeak Ling Ding2, Bernadette Byrne3
1Department of Life Sciences, Imperial College London, SW7 2AZ, UK; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Biochimica Et Biophysica Acta
|November 24, 2015
Summary
Sterile alpha- and armadillo-motif-containing protein (SARM) suppresses innate immune signaling by interacting with Toll-like receptor (TLR) adaptors MyD88 and TRIF. A specific glycine residue in SARM is crucial for this interaction and immune suppression.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Toll-like receptors (TLRs) initiate innate immunity via adaptor proteins.
- Sterile alpha- and armadillo-motif-containing protein (SARM) uniquely suppresses immune signaling.
Purpose of the Study:
- To investigate SARM's interaction with TLR adaptors MyD88 and TRIF.
- To identify key residues and motifs involved in SARM's inhibitory function.
Main Methods:
- Recombinant expression and purification of SARM TIR domain.
- In vitro interaction assays with MyD88 and TRIF.
- HEK293 cell transfections to assess cytokine upregulation (IL-8, TNF-α) and TLR2 stimulation.
Main Results:
- SARM TIR domain directly interacts with MyD88 and TRIF.
- Glycine at position 601 (G601) in the SARM BB-loop is essential for interaction.
- SARM suppresses LPS- and LTA-induced cytokine production, an effect dependent on G601.
- SARM inhibits both MyD88- and TRIF-dependent TLR signaling pathways.
Conclusions:
- SARM targets a broader range of immune signaling proteins than previously known.
- The BB-loop motif of SARM is critical for its immune-suppressive function.
- Findings provide insight into endogenous mechanisms controlling inflammation.
Keywords:
ImmunomodulationInnate immunitySterile α and armadillomotifcontaining protein (SARM)TIR domainTLR signallingMore Related Videos
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