SPATIOTEMPORAL REGULATION OF RP105 SUBCELLULAR LOCALIZATION SHAPES ENDOSOMAL TLR4 SIGNALING

Abstract Innate immune sensing of microbial and endogenous ligands by Toll-like receptor (TLR) 4 drives inflammation antimicrobial mechanisms. While critical for host defense against pathogens, unchecked TLR4 activation causes organ damage chronic disease. Molecular mechanisms that drive versus turn off activity are being pursued as potential targets preventing treating infections inflammation-driven pathologies. Mechanisms the temporal spatial regulation signaling originating from cell surface well established. In contrast, endosomal compartments is not known. Here we show TLR-related receptor, Radioprotective 105 kDa (RP105), localizes to TLR4-containing in murine macrophages. RP105 has been proposed a negative regulator TLR4-MyD88 surface, but whether it modulates unknown. Our data shows RP105-deficiency reduces LPS- E. coli-induced type I IFN responses, suggesting facilitates TLR4-TRIF signaling. We employed high-resolution microscopy AI-guided quantitative analyses interrogate spatiotemporal relationship between compartments. Cellular led transient reduction results suggest via TRIF mediates this process, MyD88. Moreover, our identify phosphatidylinositol 3-kinase p110-delta Bruton’s tyrosine kinase regulators localization. Collectively, positive AAI Careers Immunology Fellowship, 2022-2023