The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance
Leeanna El-Houjeiri,
Elite Possik,
Tarika Vijayaraghavan,
Mathieu Paquette,
José A. Martina,
Jalal M. Kazan,
Eric H. Ma,
Russell Jones,
Paola Blanchette,
Rosa Puertollano,
Arnim Pause
Affiliations
Leeanna El-Houjeiri
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Elite Possik
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Tarika Vijayaraghavan
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Mathieu Paquette
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
José A. Martina
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Jalal M. Kazan
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Eric H. Ma
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada
Russell Jones
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada
Paola Blanchette
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Rosa Puertollano
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Arnim Pause
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada; Corresponding author
Summary: TFEB and TFE3 are transcriptional regulators of the innate immune 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/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK confers pathogen resistance via activation of TFEB/TFE3-dependent antimicrobial genes, whereas ablation of total AMPK activity abolishes this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induces 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 AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status with innate immunity. : El-Houjeiri et al. show that loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression and phagocytosis in macrophages and confers pathogen resistance in C. elegans. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status to innate immunity. Keywords: TFEB, TFE3, FLCN, AMPK, innate immune response, pathogen resistance, autophagy, lysosomal biogenesis, phagocytosis
