Journal Article

DZNE-2024-00216

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png UNC93B1 variants underlie TLR7-dependent autoimmunity.

Wolf, C. ; Lim, E. L. ; Mokhtari, M. ; Kind, B. ; Odainic, A. ; Lara-Villacanas, E. ; Koss, S. ; Mages, S. ; Menzel, K. ; Engel, K. ; Dückers, G. ; Bernbeck, B. ; Schneider, D. T. ; Siepermann, K. ; Niehues, T. ; Goetzke, C. C. ; Durek, P. ; Minden, K. ; Dörner, T. ; Stittrich, A. ; Szelinski, F. ; Guerra, G. M. ; Massoud, M. ; Bieringer, M. ; de Oliveira Mann, C. C. ; Beltrán, E. ; Kallinich, T. ; Mashreghi, M.-F. ; Schmidt, S. V. ; Latz, E.DZNE* ; Klughammer, J. ; Majer, O. ; Lee-Kirsch, M. A.

2024
AAAS Washington, DC

This record in other databases:    

Please use a persistent id in citations: doi:10.1126/sciimmunol.adi9769

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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Toll-Like Receptor 7: genetics (MeSH) ; Autoimmunity: genetics (MeSH) ; Toll-Like Receptor 9: metabolism (MeSH) ; Toll-Like Receptor 8 (MeSH) ; Toll-Like Receptor 3: metabolism (MeSH) ; Lupus Erythematosus, Systemic: genetics (MeSH) ; Membrane Transport Proteins (MeSH) ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Toll-Like Receptor 8 ; Toll-Like Receptor 3 ; TLR7 protein, human ; UNC93B1 protein, human ; Membrane Transport Proteins ; UNC93B1 protein, mouse

---

Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2024

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---