Macrophages downregulate NEDD9 to counteract S. Typhimurium- mediated FAK-AKT activation and lysosome inhibition.

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium (ST)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network. Bacterial infections induced host-mediated lysosomal degradation of NEDD9 in macrophages and PBMCs isolated from patients suffering from bloodstream infection. However, ST induced translocation of NEDD9 from the cytoplasm to ST-containing phagosomes and prevented their phagolysosome-mediated clearance by FAK/AKT activation, reflecting a bacterial evasion mechanism. Complete loss of NEDD9 significantly reduced bacterial burden and enhanced inflammation upon ST infection both in vitro and in vivo. Mechanistically, we show that NEDD9 activates the FAK-AKT pathway allowing phosphorylation of FAK and AKT to impair phagolysosomal-mediated clearance of bacteria. Our study has thus identified NEDD9 as a critical regulator of lysosomal function in macrophages and a potential host-directed therapeutic target to treat bacterial infections.Classification: Biological Sciences, Microbiology Macrophages downregulate NEDD9 to counteract ST mediated FAK-AKT activation. Upon infection with ST NEDD9 is translocated from the cytosol to ST-containing phagosomes. Loss of NEDD9 results in enhanced lysosomal capacities supporting bacterial clearance. Strikingly, ST recruits and activates FAK and AKT to suppress endosome-lysosome fusion, thereby bypassing lysosome-mediated pathogen clearance. Created in BioRender. Robinson, N. (2021) BioRender.com/n17r483.