UNC93B1 chaperone fine-tunes TLR7 and TLR9 trafficking and SLE tolerance

A 50-minute expert lecture on the ImmuneZoom YouTube channel explains how UNC93B1, a 12-transmembrane chaperone for endosomal TLRs, differentially regulates TLR trafficking and function. Activated TLR7-RNA complexes are routed to multivesicular bodies to restrain self-RNA sensing, while TLR9 activation depends on a palmitoylation-depalmitoylation checkpoint. Mis-sense UNC93B1 mutations such as D93I and R336 drive TLR7 hyperactivation and lupus-like disease in mice, matching early-onset SLE in humans, and blocking the checkpoint with DHHC or PPT1 knockdown, HDSS or TPS1 inhibitors cuts type I interferon and cytokines in spontaneous SLE mice and patient PBMCs.