Max Planck Institute for Infection Biology, Berlin 10117, Germany.
Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany.
Sci Immunol. 2024 Feb 23;9(92):eadi9575. doi: 10.1126/sciimmunol.adi9575.
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 a 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 is associated with 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 in preventing pathological TLR7 signaling and autoimmune disease.
过度活跃的 TLR7 信号一直被认为是导致小鼠模型自身免疫疾病的驱动因素。最近，TLR7 的获得性功能突变被确定为人类狼疮的单基因病因。TLR7 是一种细胞内跨膜受体，在晚期内体中感应 RNA 断裂产物。在这里，我们表明内体功能障碍导致不受限制的 TLR7 信号，并与人类狼疮有关。晚期内体 BORC 复合物与小 GTPase Arl8b 通过调节受体周转率来控制细胞内 TLR7 水平。这需要 TLR7 相关运输因子 Unc93b1 和 Arl8b 之间的直接相互作用。我们在一名儿童期发病的狼疮患者中鉴定出 UNC93B1 突变，这导致 BORC 相互作用减少和内体 TLR7 积累。因此，控制 TLR7 周转率的失败足以打破对核酸的免疫耐受。我们的研究结果强调了完整的内膜系统在防止病理性 TLR7 信号和自身免疫疾病中的重要性。
