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

Abstract

At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA or 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 1 . 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 signaling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. We find that mutations in Unc93b1 leading to enhanced TLR7 signaling 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 signaling. Syntenin-1 binding requires phosphorylation of Unc93b1, providing a mechanism for dynamic regulation of TLR7 activation and signaling. Thus, Unc93b1 not only enables proper trafficking of nucleic acidsensing TLRs but also sets the activation threshold of potentially self-reactive TLR7.Recognition of nucleic acids enables detection of diverse pathogens by a limited number of innate immune receptors but also exposes the host to potential autoimmunity 2,3 . Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE)

“…SDCBP interacts with both UNC93B1 and TLR7 [30]. This interaction dampens TLR7 signaling and prevents autoimmune activation of TLR7 by endogenous nucleic acids [30,35]. Gene-edited mice expressing a mutant Unc93B1 in which three critical amino acids of this C-terminal domain were altered (530-PKP/AAA-532) developed hallmarks of systemic inflammation and autoimmunity [30], similar to what has been observed in Tlr7 overexpressing mice [38][39][40].…”

“…A 33 amino acid sequence motif in the cytoplasmic C-terminal domain of UNC93B1 binds to syndecan binding protein (SDCBP), also called syntenin-1. SDCBP interacts with both UNC93B1 and TLR7 [30]. This interaction dampens TLR7 signaling and prevents autoimmune activation of TLR7 by endogenous nucleic acids [30,35].…”

“…We performed a new GWAS and obtained the strongest association signal on the same chromosome, but approximately 1 Mb more proximal than the location in the previously reported GWAS [20]. Given that linkage disequilibrium within breeds can span several Mb, we consider our [30]. The proline at position 480 of the canine UNC93B1 protein is strictly conserved across all vertebrates.…”

“…We confirmed the variant by Sanger sequencing (Figure 3). [30]. The proline at position 480 of the canine UNC93B1 protein is strictly conserved across all vertebrates.…”

“…The sequences were derived from the following database accessions: dog XP_540813.3, human NP_112192.2, cow XP_540813.3, horse XP_023510352.1, mouse NP_062322.2, rat NP_001101983.1, chicken XP_004941322.1, frog NP_001093723.1, zebrafish XP_0026660582.1. (C) Scanning-alanine mutagenesis in mouse macrophages identified four mutants that disrupt SDCBP binding and lead to upregulated TLR7 signaling [30]. The altered residues in these mutants are underlined.…”