UC Berkeley

UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. In this dissertation, I introduce the field of innate immunity, endosomal TLRs, and the known roles of UNC93B1. Furthermore, I discuss results from our studies to understand the mechanism by which UNC93B1 mediates its regulatory effects. Our results demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. In addition, we established several assays to determine UNC93B1 function and describe a mouse model to better understand the regulation of an endogenous nucleic acid sensing TLR, TLR9. Our studies describe mechanisms for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases.