Disrupted degradative sorting of TLR7 is associated with human lupus
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Science immunology - 9(2024), 92 vom: 23. Feb., Seite eadi9575 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mishra, Harshita [VerfasserIn] |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciimmunol.adi9575 |
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| Förderinstitution / Projekttitel: |
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NLM366976028 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Thieck, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Magg, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Raedler, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Ewers, Helge |e verfasserin |4 aut | |
| 700 | 1 | |a Lee-Kirsch, Min Ae |e verfasserin |4 aut | |
| 700 | 1 | |a Meierhofer, David |e verfasserin |4 aut | |
| 700 | 1 | |a Hauck, Fabian |e verfasserin |4 aut | |
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