Humans and animals are constantly exposed to pathogenic microorganisms that can enter the body and cause disease. Mechanisms of defense against invading pathogens are essential for all living organisms to propagate and survive. The transcription factor EB (TFEB), a master transcriptional regulator of lysosomal and autophagic pathways, has been recently shown to play a critical role in innate immunity both in Caenorhabditis elegans (C. elegans) and mammals. Despite the important role (s) of TFEB in physiological and pathological states including neurodegenerative diseases, immunity, and cancer, its upstream regulation is not fully elucidated. Here, we show that FLCN-1 and its binding partner 5'AMP-activated protein kinase (AMPK) regulate HLH-30, the TFEB worm homolog. FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dube (BHD) tumor syndrome. Using C. elegans, we show that
flcn-1 mutant animals exhibit an increased resistance to bacterial pathogens in an
hlh-30-dependent manner. Loss of
flcn-1 induces the nuclear translocation of HLH-30 upon infection with Staphylococcus aureus, which increases the transcription of antimicrobial genes. We further show that this phenotype is independent of mTOR. Using RNA-Seq technology, we demonstrate that AMPK regulates a subset of the
hlh-30-dependent antimicrobial peptide genes. Accordingly, loss of AMPK decreases the HLH-30 nuclear translocation and suppresses the increased resistance of
flcn-1 mutant animals to Staphylococcus aureus and Pseudomonas aeruginosa. Importantly, our findings highlight that this pathway is evolutionarily conserved. Specifically, we show that loss of Flcn in mouse embryonic fibroblasts also induces the nuclear translocation of TFEB/TFE3 and the upregulation of inflammatory cytokines in an mTOR independent manner. Overall, our findings support an important role for FLCN and AMPK in the regulation of TFEB, which is a central mechanism of resistance to pathogenic agents.