%0 Journal Article
%A Wolf, Christine
%A Lim, Ee Lyn
%A Mokhtari, Mohammad
%A Kind, Barbara
%A Odainic, Alexandru
%A Lara-Villacanas, Eusebia
%A Koss, Sarah
%A Mages, Simon
%A Menzel, Katharina
%A Engel, Kerstin
%A Dückers, Gregor
%A Bernbeck, Benedikt
%A Schneider, Dominik T
%A Siepermann, Kathrin
%A Niehues, Tim
%A Goetzke, Carl Christoph
%A Durek, Pawel
%A Minden, Kirsten
%A Dörner, Thomas
%A Stittrich, Anna
%A Szelinski, Franziska
%A Guerra, Gabriela Maria
%A Massoud, Mona
%A Bieringer, Markus
%A de Oliveira Mann, Carina C
%A Beltrán, Eduardo
%A Kallinich, Tilmann
%A Mashreghi, Mir-Farzin
%A Schmidt, Susanne V
%A Latz, Eicke
%A Klughammer, Johanna
%A Majer, Olivia
%A Lee-Kirsch, Min Ae
%T UNC93B1 variants underlie TLR7-dependent autoimmunity.
%J Science immunology
%V 9
%N 92
%@ 2470-9468
%C Washington, DC
%I AAAS
%M DZNE-2024-00216
%P eadi9769
%D 2024
%X 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.
%K Mice
%K Animals
%K Humans
%K Toll-Like Receptor 7: genetics
%K Autoimmunity: genetics
%K Toll-Like Receptor 9: metabolism
%K Toll-Like Receptor 8
%K Toll-Like Receptor 3: metabolism
%K Lupus Erythematosus, Systemic: genetics
%K Membrane Transport Proteins
%K Toll-Like Receptor 7 (NLM Chemicals)
%K Toll-Like Receptor 9 (NLM Chemicals)
%K Toll-Like Receptor 8 (NLM Chemicals)
%K Toll-Like Receptor 3 (NLM Chemicals)
%K TLR7 protein, human (NLM Chemicals)
%K UNC93B1 protein, human (NLM Chemicals)
%K Membrane Transport Proteins (NLM Chemicals)
%K UNC93B1 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38207055
%R 10.1126/sciimmunol.adi9769
%U https://pub.dzne.de/record/268464