% IMPORTANT: The following is UTF-8 encoded. This means that in the presence % of non-ASCII characters, it will not work with BibTeX 0.99 or older. % Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or % “biber”. @ARTICLE{Wolf:268464, author = {Wolf, Christine and Lim, Ee Lyn and Mokhtari, Mohammad and Kind, Barbara and Odainic, Alexandru and Lara-Villacanas, Eusebia and Koss, Sarah and Mages, Simon and Menzel, Katharina and Engel, Kerstin and Dückers, Gregor and Bernbeck, Benedikt and Schneider, Dominik T and Siepermann, Kathrin and Niehues, Tim and Goetzke, Carl Christoph and Durek, Pawel and Minden, Kirsten and Dörner, Thomas and Stittrich, Anna and Szelinski, Franziska and Guerra, Gabriela Maria and Massoud, Mona and Bieringer, Markus and de Oliveira Mann, Carina C and Beltrán, Eduardo and Kallinich, Tilmann and Mashreghi, Mir-Farzin and Schmidt, Susanne V and Latz, Eicke and Klughammer, Johanna and Majer, Olivia and Lee-Kirsch, Min Ae}, title = {{UNC}93{B}1 variants underlie {TLR}7-dependent autoimmunity.}, journal = {Science immunology}, volume = {9}, number = {92}, issn = {2470-9468}, address = {Washington, DC}, publisher = {AAAS}, reportid = {DZNE-2024-00216}, pages = {eadi9769}, year = {2024}, abstract = {UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.}, keywords = {Mice / Animals / Humans / Toll-Like Receptor 7: genetics / Autoimmunity: genetics / Toll-Like Receptor 9: metabolism / Toll-Like Receptor 8 / Toll-Like Receptor 3: metabolism / Lupus Erythematosus, Systemic: genetics / Membrane Transport Proteins / Toll-Like Receptor 7 (NLM Chemicals) / Toll-Like Receptor 9 (NLM Chemicals) / Toll-Like Receptor 8 (NLM Chemicals) / Toll-Like Receptor 3 (NLM Chemicals) / TLR7 protein, human (NLM Chemicals) / UNC93B1 protein, human (NLM Chemicals) / Membrane Transport Proteins (NLM Chemicals) / UNC93B1 protein, mouse (NLM Chemicals)}, cin = {AG Latz ; AG Latz}, ddc = {610}, cid = {I:(DE-2719)1013024}, pnm = {351 - Brain Function (POF4-351)}, pid = {G:(DE-HGF)POF4-351}, typ = {PUB:(DE-HGF)16}, pubmed = {pmid:38207055}, doi = {10.1126/sciimmunol.adi9769}, url = {https://pub.dzne.de/record/268464}, }