UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity.

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2019
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Abstract
At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and DNA, respectively. Despite the structural and functional similarities between these receptors, their contribution to autoimmune diseases such as systemic lupus erythematosus (SLE) can be quite different. For example, TLR7 and TLR9 have opposing effects in mouse models of SLE; disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice. However, mechanisms of negative regulation that differentiate between TLR7 and TLR9 have not been described. Here we report a new function for the TLR trafficking chaperone UNC93B1 that specifically limits signalling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. We find that mutations in UNC93B1 leading to enhanced TLR7 signalling also disrupt binding to syntenin-1, a protein implicated in exosome biogenesis. Both UNC93B1 and TLR7 are detectable in exosomes, suggesting that UNC93B1 recruitment of Syntenin-1 facilitates sorting of TLR7 into intralumenal vesicles of multivesicular bodies, which terminates signalling. Syntenin-1 binding requires phosphorylation of UNC93B1, providing a mechanism for dynamic regulation of TLR7 activation and signalling. Thus, UNC93B1 not only enables proper trafficking of nucleic acid-sensing TLRs but also sets the activation threshold of potentially self-reactive TLR7.
Reference Key
majer2019unc93b1nature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Majer, Olivia;Liu, Bo;Kreuk, Lieselotte S M;Krogan, Nevan;Barton, Gregory M;
Journal Nature
Year 2019
DOI
10.1038/s41586-019-1612-6
URL
Keywords
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