The Toll-like receptors (TLRs) TLR7 and TLR9 are known to have a role in the sensing of an organism's own nucleic acids in autoimmune diseases such as systemic lupus erythematosus. Mice lacking these TLRs have opposing roles in mouse models of systemic lupus erythematosus, as disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice, suggesting that TLR7 and TLR9 are differentially regulated. Despite this, the mechanisms that distinguish signalling downstream of these TLRs are unknown. Competition for the chaperone UNC93B1, which is thought to function exclusively as a trafficking factor that mediates the delivery of newly synthesized nucleic-acid-binding TLRs to endosomes, has been proposed as a mechanism to account for the differential roles of these TLRs in vivo. However, this remained controversial, and in these studies Gregory Barton and colleagues show that UNC93B1 interacts with syntenin-1 to facilitate the sorting of TLR7–UNC93B1 complexes into intraluminal vesicles of multivesicular bodies. Internalization into multivesicular bodies is thought to terminate TLR7 signalling, and disruption of the UNC93B1–syntenin-1 interaction in mice is shown to result in TLR7-dependent autoimmunity. By contrast, release from UNC93B1 in endosomes is required for the activation of TLR9, reducing the likelihood that it will be activated by extracellular DNA.
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