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UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity
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UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity
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Journal Article
UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity
2019
Overview
At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and self-DNA, respectively. Despite the structural and functional similarities between these receptors, their contributions to autoimmune diseases such as systemic lupus erythematosus can differ. For example, TLR7 and TLR9 have opposing effects in mouse models of systemic lupus erythematosus—disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice
1
. However, the mechanisms of negative regulation that differentiate between TLR7 and TLR9 are unknown. Here we report a function for the TLR trafficking chaperone UNC93B1 that specifically limits signalling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. Mutations in UNC93B1 that lead to enhanced TLR7 signalling also disrupt binding of UNC93B1 to syntenin-1, which has been implicated in the biogenesis of exosomes
2
. Both UNC93B1 and TLR7 can be detected in exosomes, suggesting that recruitment of syntenin-1 by UNC93B1 facilitates the sorting of TLR7 into intralumenal vesicles of multivesicular bodies, which terminates signalling. Binding of syntenin-1 requires phosphorylation of UNC93B1 and provides a mechanism for dynamic regulation of TLR7 activation and signalling. Thus, UNC93B1 not only enables the proper trafficking of nucleic acid-sensing TLRs, but also sets the activation threshold of potentially self-reactive TLR7.
The interaction of UNC93B1 with syntenin-1 facilitates the sorting of TLR7–UNC93B1 complexes into intraluminal vesicles of multivesicular bodies, and mutations in UNC93B1 that disrupt such interactions lead to enhanced TLR7 signalling and autoimmunity.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 13/21
/ 13/31
/ 13/95
/ 14/63
/ 64/60
/ 82/29
/ 82/58
/ 82/83
/ Acids
/ Analysis
/ Animals
/ Binding
/ Control
/ DNA
/ Exosomes
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Lupus
/ Membrane Glycoproteins - metabolism
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Mice
/ Mutation
/ Polymorphism, Single Nucleotide
/ Protein-protein interactions
/ Proteins
/ RNA
/ Science
/ Structure-function relationships
/ Systemic lupus erythematosus
/ TLR7
