The ups and downs of human UNC93B1: Autoimmune and viral conditions

Mouse Unc93b1 was identified in 2006 by forward genetics as an ER membrane protein essential for the activity of the endosomal nucleic acid-sensing receptors TLR3, TLR7, and TLR9. In vitro studies in mouse and human cells have revealed its cellular functions, including ER-based stabilization and trafficking of endosomal TLR proteins (TLR3, TLR7, TLR8, and TLR9) and regulation of signaling thresholds through competitive trafficking control (TLR7 and TLR9). Human genetic studies have clarified the physiological role of UNC93B1 in natural conditions. Biallelic loss-of-function UNC93B1 mutations impair TLR3 signaling in central nervous system-resident cells, thereby conferring a predisposition to HSV-1 encephalitis. UNC93B1 deficiency may also predispose to other viral infections, as suggested by patients with inherited TLR3 or TLR7 deficiency. Conversely, monoallelic or biallelic UNC93B1 gain-of-function variants enhancing TLR7 and/or TLR8 signaling predispose patients to autoimmunity and inflammation, including early-onset systemic lupus erythematosus and chilblain lupus. Thus, in humans, UNC93B1 maintains a delicate balance between host defense and tolerance to self.