PT  - JOURNAL ARTICLE
AU  - Leeanna El-Houjeiri
AU  - Elite Possik
AU  - Tarika Vijayaraghavan
AU  - Mathieu Paquette
AU  - José A Martina
AU  - Jalal M. Kazan
AU  - Eric H. Ma
AU  - Russell Jones
AU  - Paola Blanchette
AU  - Rosa Puertollano
AU  - Arnim Pause
TI  - The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance
AID  - 10.1101/463430
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 463430
4099  - http://biorxiv.org/content/early/2018/11/06/463430.short
4100  - http://biorxiv.org/content/early/2018/11/06/463430.full
AB  - 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 conferred pathogen resistance via activation of TFEB/TFE3-dependent antimicrobial genes, while ablation of total AMPK activity abolished this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induced TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages was 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.