Cell Reports
Volume 26, Issue 13, 26 March 2019, Pages 3613-3628.e6
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Article
The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance

https://doi.org/10.1016/j.celrep.2019.02.102Get rights and content
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Highlights

  • AMPK and FLCN regulate TFEB/TFE3-mediated innate immunity and pathogen resistance

  • Loss of FLCN or activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory profile

  • FLCN depletion in macrophages enhances their energy metabolism and phagocytosis

  • LPS treatment induces acute ATP reduction followed by AMPK and TFEB activation

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.

Keywords

TFEB
TFE3
FLCN
AMPK
innate immune response
pathogen resistance
autophagy
lysosomal biogenesis
phagocytosis

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These authors contributed equally

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