Invading Bacterial Pathogens Activate Transcription Factor EB in Epithelial Cells Through the Amino Acid Starvation Pathway of MTORC1 Inhibition

Upon pathogen infection, intricate innate signaling cascades are induced to initiate the transcription of immune effectors, including cytokines and chemokines. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy genes, was found recently to be a novel regulator of innate immunity in both Caenorhabditis elegans and mammals. Despite TFEB participating in critical mechanisms of pathogen recognition and in the transcriptional response to infection in mammalian macrophages, little is known about its roles in the infected epithelium or infected nonimmune cells in general. Here, we demonstrate that TFEB is activated in nonimmune cells upon infection with bacterial pathogens through a pathway dependent on mTORC1 inhibition and RAG-GTPase activity, reflecting the importance of membrane damage and amino acid starvation responses during infection. Additionally, we present data demonstrating that although TFEB does not affect bacterial killing or load in nonimmune cells, it alters the host transcriptome upon infection, thus promoting an antibacterial transcriptomic landscape. Elucidating the roles of TFEB in infected nonimmune cells and the upstream signaling cascade provides critical insight into understanding how cells recognize and respond to bacterial pathogens.