title: Processing of human toll-like receptor 7 by furin-like proprotein convertases is required for its accumulation and activity in endosomes.
abstract: Toll-like receptor 7 (TLR7) triggers antiviral immune responses by recognizing viral single-stranded RNA in endosomes, but the biosynthetic pathway of human TLR7 (hTLR7) remains unclear. Here, we show that hTLR7 is proteolytically processed and that the C-terminal fragment selectively accumulates in endocytic compartments. hTLR7 processing occurred at neutral pH and was dependent on furin-like proprotein convertases (PCs). Furthermore, TLR7 processing was required for its functional response to TLR7 agonists such as R837 or influenza virus. Notably, proinflammatory and differentiation stimuli increased the expression of furin-like PCs in immune cells, suggesting a positive feedback mechanism for TLR7 processing during infection. Because self-RNA can under certain conditions activate TLR7 and trigger autoimmunity, our results identify furin-like PCs as a possible target to attenuate TLR7-dependent autoimmunity and other immune pathologies.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Madeleine M
authors.initials: MM
authors.lastname: Hipp
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: Michael C
authors.initials: MC
authors.lastname: Aichinger
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.forename: Mariola J
authors.initials: MJ
authors.lastname: Edelmann
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Caetano
authors.initials: C
authors.lastname: Reis e Sousa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000595:Amino Acid Sequence; D015551:Autoimmunity; D002460:Cell Line; D011992:Endosomes / Q000187:drug effects / Q000276:immunology; D025461:Feedback, Physiological; D045683:Furin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009975:Orthomyxoviridae / Q000276:immunology; D043484:Proprotein Convertases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C557465:1-(2-methylpropyl)-1H-imidazo(4,5-c)quinolin 4-amine; D011804:Quinolines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D043484:Proprotein Convertases; D045683:Furin