2.A.1.58.7
Unc-93 family homologue B1, Unc-93b1 or Unc93b1, of 597 aas and 12 TMSs, plays a role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling (Pelka et al. 2014). It is required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the endoplasmic reticulum to endolysosomes where they can engage pathogen nucleotides (e.g., of viral nucleic acids) and activate signaling cascades. Unc93B1 may play a role in autoreactive B-cells removal (Isnardi et al. 2008).  It induces apoptotic cell death and is cleaved by host and viral proteases (Harris and Coyne 2015). UNC93B1 may play a role in human oral squamous cell carcinomas growth by controlling the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF) (Wagai et al. 2019). UNC93B1 regulates Toll-like receptor stability independently of endosomal TLR transport (Pelka et al. 2018). A missense variant affecting the C-terminal tail of UNC93B1 in dogs is responsible for a Exfoliative Cutaneous Lupus Erythematosus (ECLE) condition (Leeb et al. 2020). Compartmentalization of TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. UNC93B1 is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome. Ishida et al. 2021 reported two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to other MFS porters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state (Ishida et al. 2021). The mammalian trafficking chaperone protein UNC93B1 maintains the ER calcium sensor STIM1 in a dimeric state primed for translocation to the ER cortex (Wang and Demaurex 2022).