UNC93B1 variants underlie TLR7-dependent autoimmunity.
Sci Immunol
; 9(92): eadi9769, 2024 Feb 23.
Article
in En
| MEDLINE
| ID: mdl-38207055
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Toll-Like Receptor 7
/
Lupus Erythematosus, Systemic
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Immunol
Year:
2024
Document type:
Article
Affiliation country:
Alemania
Country of publication:
Estados Unidos