YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro
Robin Caire, Estelle Audoux, Mireille Thomas, Elisa Dalix, Aurélien Peyron, Killian Rodriguez, Nicola Pordone, Johann Guillemot, Yann Dickerscheit, Hubert Marotte, François Vandenesch, Frédéric Laurent, Jérôme Josse, Paul O. Verhoeven
Abstract
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 then 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 key insights on the anti-S. aureus activity of YAP, which could be conserved for defense against other intracellular bacteria.