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

Cell Rep. 2019 Mar 26;26(13):3613-3628.e6. doi: 10.1016/j.celrep.2019.02.102.


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

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line
  • Disease Resistance
  • Immunity, Innate* / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins / metabolism*
  • Tumor Suppressor Proteins / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Bhd protein, mouse
  • Caenorhabditis elegans Proteins
  • HLH-30 protein, C elegans
  • Proto-Oncogene Proteins
  • Tcfeb protein, mouse
  • Tumor Suppressor Proteins
  • Tcfe3 protein, mouse
  • AMP-Activated Protein Kinases