SRP372748 PRJNA833123 GSE201826 p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation In addition to the role in lysosomal biogenesis and autophagy, TFEB has been described to participate in the control of inflammation and host defense against pathogen infection The activation of TFEB in toll-like receptor-induced or bacteria exposed macrophages is regulated by a mechanism independent of mTORC1 inactivation, suggesting that other protein kinases may participate in the regulation of TFEB function during macrophage activation In this study, we identified a novel role of p38 MAPK in TFEB regulation. We showed p38-dependent TFEB phosphorylation at serine 401 (S401) in response to a variety of stress conditions, including oxidative stress, UVC irradiation, growth factors, and lipopolysaccharide (LPS) treatment. Furthermore, inhibition of S401 phosphorylation during PMA-induced monocyte differentiation prevented TFEB nuclear accumulation and resulted in reduced expression of multiple immune genes. TFEB-S401A expressing M0 macrophages also failed to efficiently polarize into M1 inflammatory macrophages, showing defective upregulation of cytokines and chemokines, as well as reduced inflammasome activation. We conclude that TFEB is a target of the p38 signaling pathway that is required for monocyte/macrophage differentiation and function. Overall design: Analysis of mRNA expression in THP1-TFEB-WT or TFEB-S401A cells in the presence or absence of PMA treatment. GSE201826 pubmed 36507874