The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance

Summary TFEBand TFE3are transcriptional regulators of the innateimmune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. Using C. elegans and mammalian models, we report that the master metabolic modulator 5′- AMP-activated protein kinase( AMPK) and its negative regulator Folliculin(FLCN) act upstream of TFEB/ TFE3in the innateimmune response, independently of the mTORC1signaling pathway. In nematodes, loss of FLCN or overexpression of AMPKconfers pathogen resistance via activation of TFEB/ TFE3-dependent antimicrobial genes, whereas ablation of total AMPKactivity abolishes this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPKinduces TFEB/ TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages is observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPKactivation and TFEBnuclear localization. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status with innateimmunity.