TY  - JOUR
AU  - Wolf, Christine
AU  - Lim, Ee Lyn
AU  - Mokhtari, Mohammad
AU  - Kind, Barbara
AU  - Odainic, Alexandru
AU  - Lara-Villacanas, Eusebia
AU  - Koss, Sarah
AU  - Mages, Simon
AU  - Menzel, Katharina
AU  - Engel, Kerstin
AU  - Dückers, Gregor
AU  - Bernbeck, Benedikt
AU  - Schneider, Dominik T
AU  - Siepermann, Kathrin
AU  - Niehues, Tim
AU  - Goetzke, Carl Christoph
AU  - Durek, Pawel
AU  - Minden, Kirsten
AU  - Dörner, Thomas
AU  - Stittrich, Anna
AU  - Szelinski, Franziska
AU  - Guerra, Gabriela Maria
AU  - Massoud, Mona
AU  - Bieringer, Markus
AU  - de Oliveira Mann, Carina C
AU  - Beltrán, Eduardo
AU  - Kallinich, Tilmann
AU  - Mashreghi, Mir-Farzin
AU  - Schmidt, Susanne V
AU  - Latz, Eicke
AU  - Klughammer, Johanna
AU  - Majer, Olivia
AU  - Lee-Kirsch, Min Ae
TI  - UNC93B1 variants underlie TLR7-dependent autoimmunity.
JO  - Science immunology
VL  - 9
IS  - 92
SN  - 2470-9468
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2024-00216
SP  - eadi9769
PY  - 2024
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Humans
KW  - Toll-Like Receptor 7: genetics
KW  - Autoimmunity: genetics
KW  - Toll-Like Receptor 9: metabolism
KW  - Toll-Like Receptor 8
KW  - Toll-Like Receptor 3: metabolism
KW  - Lupus Erythematosus, Systemic: genetics
KW  - Membrane Transport Proteins
KW  - Toll-Like Receptor 7 (NLM Chemicals)
KW  - Toll-Like Receptor 9 (NLM Chemicals)
KW  - Toll-Like Receptor 8 (NLM Chemicals)
KW  - Toll-Like Receptor 3 (NLM Chemicals)
KW  - TLR7 protein, human (NLM Chemicals)
KW  - UNC93B1 protein, human (NLM Chemicals)
KW  - Membrane Transport Proteins (NLM Chemicals)
KW  - UNC93B1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38207055
DO  - DOI:10.1126/sciimmunol.adi9769
UR  - https://pub.dzne.de/record/268464
ER  -