O44

Endosome dysfunction leads to gain-of-function TLR7 and human lupus

MISHRA H. ², SCHLACK-LEIGERS C. ³, LIM E. ², THIECK O. ², MAGG T. ¹, RAEDLER J. ¹, WOLF C. ⁵, KLEIN C. ¹, EWERS H. ³, LEE-KIRSCH M. ⁵, MEIERHOFER D. ⁴, HAUCK F. ¹, MAJER O. ²

¹ Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; ² Max Planck Institute for Infection Biology, Berlin, Germany; ³ Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; ⁴ Max Planck Institute for Molecular Genetics, Berlin, Germany; ⁵ Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease