YAP promotes cell-autonomous immune responses in vitro to tackle intra-cellular Staphylococcus aureus

Transcriptional cofactors YAP/TAZ have recently been found to support autophagy and inflammation, which are part of cell autonomous immunity and are critical in antibacterial defense. Here, we studied the role of YAP against Staphylococcus aureus using CRISPR/Cas9-mutated HEK293 cells and a primary cell-based organoid model. We found that S. aureus infection increases YAP transcriptional activity, which is required to reduce intracellular S. aureus replication. A 770-gene targeted transcriptomic analysis revealed that YAP upregulates genes involved in autophagy/lysosome and inflammation pathways in both infected and uninfected conditions. The YAP/TEAD transcriptional activity promotes autophagic flux and lysosomal acidification, which are important for defense against intracellular S. aureus. Furthermore, the staphylococcal toxin C3 exoenzyme EDIN-B was found effective in preventing YAP-mediated cell-autonomous immune response. This study provides new insights on the anti-S. aureus activity of YAP, which could be conserved for defense against other intracellular bacteria. HEK293 cells wild type (WT) or YAP knockout (YAP KO or YAP-/-), control (CTRL) or S. aureus (SA) infected were used. 12 samples were analyzed corresponding to 4 groups: WT CTRL, YAPKO CTRL, WT SA, YAPKO SA with n=3 samples per group. nCounter Nanostring host response panel was used to analyse the expression of 770 genes. 4 comparisions were made between groups : WT CTRL vs WT SA; WT CTRL vs YAPKO CTRL; YAPKO CTRL vs YAPKO SA; WT SA vs YAPKO SA