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RSS FeedsTRAF3-interacting JNK-activating modulator promotes inflammation by stimulating translocation of Toll-like receptor 4 to lipid rafts [Signal Transduction] (Journal of Biological Chemistry)

 
 

22 february 2019 10:00:14

 
TRAF3-interacting JNK-activating modulator promotes inflammation by stimulating translocation of Toll-like receptor 4 to lipid rafts [Signal Transduction] (Journal of Biological Chemistry)
 


Toll-like receptors (TLRs) are key players of the innate immune system and contribute to inflammation and pathogen clearance. Although TLRs have been extensively studied, it remains unclear how exactly bacterial lipopolysaccharide (LPS)-induced conformational changes of the extracellular domain of the TLRs trigger the dimerization of their intracellular domain across the plasma membrane and thereby stimulate downstream signaling. Here, using LPS-stimulated THP-1-derived macrophages and murine macrophages along with immunoblotting and immunofluorescence and quantitative analyses, we report that in response to inflammatory stimuli, the coiled-coil protein TRAF3-interacting JNK-activating modulator (T3JAM) associates with TLR4, promotes its translocation to lipid rafts, and thereby enhances macrophage-mediated inflammation. T3JAM overexpression increased and T3JAM depletion decreased TLR4 signaling through both the MyD88-dependent pathway and TLR4 endocytosis. Importantly, deletion or mutation of T3JAM to disrupt its coiled-coil-mediated homoassociation abrogated TLR4 recruitment to lipid rafts. Consistently, T3JAM depletion in mice dampened TLR4 signaling and alleviated LPS-induced inflammatory damage. Collectively, our findings reveal an additional molecular mechanism by which TLR4 activity is regulated and suggest that T3JAM may function as a molecular clamp to `tighten up` TLR4 and facilitate its translocation to lipid rafts.


 
38 viewsCategory: Biochemistry
 
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