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

• DOI: 10.1038/s41467-022-34432-0
• Publication Date: 2022-11-16T12:03:43Z
• Authors: 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
• Keywords: Inflammation; 0301 basic medicine; 570; Staphylococcus aureus; Immunity, Cellular; [SDV]Life Sciences [q-bio]; Science; Q; 610; YAP-Signaling Proteins; [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy; Staphylococcal Infections; Article; 3. Good health; 03 medical and health sciences; HEK293 Cells; [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system; Trans-Activators; Humans; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Transcription Factors

AbstractTranscriptional 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 againstStaphylococcus aureususing CRISPR/Cas9-mutated HEK293 cells and a primary cell-based organoid model. We found thatS. aureusinfection increases YAP transcriptional activity, which is required to reduce intracellularS. aureusreplication. 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 intracellularS. 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. aureusactivity of YAP, which could be conserved for defense against other intracellular bacteria.