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• W2900253406 abstract "•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 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. 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. Innate immune responses constitute the first line of defense against pathogenic infections in simple metazoans, invertebrates, and mammals (Akira et al., 2006Akira S. Uematsu S. Takeuchi O. Pathogen recognition and innate immunity.Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (8720) Google Scholar, Hoffmann, 2003Hoffmann J.A. The immune response of Drosophila.Nature. 2003; 426: 33-38Crossref PubMed Scopus (1129) Google Scholar, Irazoqui et al., 2010bIrazoqui J.E. Urbach J.M. Ausubel F.M. Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates.Nat. Rev. Immunol. 2010; 10: 47-58Crossref PubMed Scopus (308) Google Scholar, Medzhitov, 2007Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (2007) Google Scholar). Although much effort has been put into elucidating the functions of downstream mediators of immune response including antimicrobial peptides, C-type lectins, cytokines, and chemokines, less is known regarding how host cells recognize foreign infections and trigger the activation of transcription factors that coordinate the anti-microbial response. Among the few well-characterized transcription factors, nuclear factor κB (NF-κB) was shown to be an important factor in controlling host defense gene expression, mediated through Toll-like receptor (TLR) and nucleotide-binding leucine-rich repeat containing (NLR) ligand pathways (Medzhitov, 2009Medzhitov R. Damage control in host-pathogen interactions.Proc. Natl. Acad. Sci. USA. 2009; 106: 15525-15526Crossref PubMed Scopus (31) Google Scholar). However, another under-appreciated host defense transcription factor was recently identified in Caenorhabditis elegans (C. elegans), which lacks the NF-κB pathway (Visvikis et al., 2014Visvikis O. Ihuegbu N. Labed S.A. Luhachack L.G. Alves A.F. Wollenberg A.C. Stuart L.M. Stormo G.D. Irazoqui J.E. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.Immunity. 2014; 40: 896-909Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Using this model, HLH-30, the C. elegans ortholog of TFEB and TFE3, was identified as an important evolutionarily conserved transcriptional regulator of the host response to infection (Lapierre et al., 2013Lapierre L.R. De Magalhaes Filho C.D. McQuary P.R. Chu C.C. Visvikis O. Chang J.T. Gelino S. Ong B. Davis A.E. Irazoqui J.E. et al.The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans.Nat. Commun. 2013; 4: 2267Crossref PubMed Scopus (303) Google Scholar, Visvikis et al., 2014Visvikis O. Ihuegbu N. Labed S.A. Luhachack L.G. Alves A.F. Wollenberg A.C. Stuart L.M. Stormo G.D. Irazoqui J.E. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.Immunity. 2014; 40: 896-909Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, Rehli et al., 1999Rehli M. Den Elzen N. Cassady A.I. Ostrowski M.C. Hume D.A. Cloning and characterization of the murine genes for bHLH-ZIP transcription factors TFEC and TFEB reveal a common gene organization for all MiT subfamily members.Genomics. 1999; 56: 111-120Crossref PubMed Scopus (74) Google Scholar). TFEB and TFE3 are basic helix-loop-helix leucine zipper transcription factors that multi-task in regulating a similar set of genes involved in lipid metabolism, autophagy, lysosomal biogenesis, and stress response genes (David, 2011David R. Autophagy: TFEB perfects multitasking.Nat. Rev. Mol. Cell Biol. 2011; 12: 404Crossref PubMed Scopus (11) Google Scholar, Raben and Puertollano, 2016Raben N. Puertollano R. TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress.Annu. Rev. Cell Dev. Biol. 2016; 32: 255-278Crossref PubMed Scopus (227) Google Scholar, Sardiello, 2016Sardiello M. Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases.Ann. N Y Acad. Sci. 2016; 1371: 3-14Crossref PubMed Scopus (81) Google Scholar, Settembre et al., 2011Settembre C. Di Malta C. Polito V.A. Garcia Arencibia M. Vetrini F. Erdin S. Erdin S.U. Huynh T. Medina D. Colella P. et al.TFEB links autophagy to lysosomal biogenesis.Science. 2011; 332: 1429-1433Crossref PubMed Scopus (2008) Google Scholar, Settembre et al., 2013Settembre C. De Cegli R. Mansueto G. Saha P.K. Vetrini F. Visvikis O. Huynh T. Carissimo A. Palmer D. Klisch T.J. et al.TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.Nat. Cell Biol. 2013; 15: 647-658Crossref PubMed Scopus (630) Google Scholar). Several studies have reported similar mechanisms underlying TFEB/TFE3 activation in response to nutrient deprivation and metabolic stress. In nutrient-rich environments, the kinases ERK2 and mTORC1 phosphorylate TFEB/TFE3 on specific serine residues and retain them in the cytoplasm in an inactive state (Martina et al., 2012Martina J.A. Chen Y. Gucek M. Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.Autophagy. 2012; 8: 903-914Crossref PubMed Scopus (783) Google Scholar, Martina et al., 2014Martina J.A. Diab H.I. Lishu L. Jeong-A L. Patange S. Raben N. Puertollano R. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris.Sci. Signal. 2014; 7: ra9Crossref PubMed Scopus (386) Google Scholar, Roczniak-Ferguson et al., 2012Roczniak-Ferguson A. Petit C.S. Froehlich F. Qian S. Ky J. Angarola B. Walther T.C. Ferguson S.M. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis.Sci. Signal. 2012; 5: ra42Crossref PubMed Scopus (838) Google Scholar, Settembre et al., 2011Settembre C. Di Malta C. Polito V.A. Garcia Arencibia M. Vetrini F. Erdin S. Erdin S.U. Huynh T. Medina D. Colella P. et al.TFEB links autophagy to lysosomal biogenesis.Science. 2011; 332: 1429-1433Crossref PubMed Scopus (2008) Google Scholar, Settembre et al., 2012Settembre C. Zoncu R. Medina D.L. Vetrini F. Erdin S. Erdin S. Huynh T. Ferron M. Karsenty G. Vellard M.C. et al.A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.EMBO J. 2012; 31: 1095-1108Crossref PubMed Scopus (1249) Google Scholar). The mTORC1-dependent phosphorylation of TFEB (S211) and TFE3 (S321) promotes binding to 14-3-3. It has been suggested that this interaction masks the nuclear localization signal (NLS), thus inhibiting TFEB and TFE3 nuclear translocation (Roczniak-Ferguson et al., 2012Roczniak-Ferguson A. Petit C.S. Froehlich F. Qian S. Ky J. Angarola B. Walther T.C. Ferguson S.M. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis.Sci. Signal. 2012; 5: ra42Crossref PubMed Scopus (838) Google Scholar, Martina et al., 2012Martina J.A. Chen Y. Gucek M. Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.Autophagy. 2012; 8: 903-914Crossref PubMed Scopus (783) Google Scholar). Conversely, under starvation, this repressive phosphorylation is lifted, resulting in their translocation to the nucleus and activation of their downstream transcriptional targets that encode components of the lysosomal biogenesis and autophagy pathways (Martina et al., 2012Martina J.A. Chen Y. Gucek M. Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.Autophagy. 2012; 8: 903-914Crossref PubMed Scopus (783) Google Scholar, Roczniak-Ferguson et al., 2012Roczniak-Ferguson A. Petit C.S. Froehlich F. Qian S. Ky J. Angarola B. Walther T.C. Ferguson S.M. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis.Sci. Signal. 2012; 5: ra42Crossref PubMed Scopus (838) Google Scholar, Settembre et al., 2011Settembre C. Di Malta C. Polito V.A. Garcia Arencibia M. Vetrini F. Erdin S. Erdin S.U. Huynh T. Medina D. Colella P. et al.TFEB links autophagy to lysosomal biogenesis.Science. 2011; 332: 1429-1433Crossref PubMed Scopus (2008) Google Scholar, Settembre et al., 2012Settembre C. Zoncu R. Medina D.L. Vetrini F. Erdin S. Erdin S. Huynh T. Ferron M. Karsenty G. Vellard M.C. et al.A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.EMBO J. 2012; 31: 1095-1108Crossref PubMed Scopus (1249) Google Scholar). Despite these remarkable similarities between TFEB and TFE3, it is still unclear whether these transcription factors have cooperative, complementary, or partially redundant roles under different environmental conditions. Importantly, in murine macrophages, both TFEB and TFE3 were shown to be activated and translocated to the nucleus upon pathogen infection or stimulation with TLR ligands, where they collaborate in mediating the transcriptional upregulation of several cytokines and chemokines involved in antimicrobial immune response (Pastore et al., 2016Pastore N. Brady O.A. Diab H.I. Martina J.A. Sun L. Huynh T. Lim J.A. Zare H. Raben N. Ballabio A. Puertollano R. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages.Autophagy. 2016; 12: 1240-1258Crossref PubMed Scopus (165) Google Scholar, Samie and Cresswell, 2015Samie M. Cresswell P. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways.Nat. Immunol. 2015; 16: 729-736Crossref PubMed Scopus (98) Google Scholar, Visvikis et al., 2014Visvikis O. Ihuegbu N. Labed S.A. Luhachack L.G. Alves A.F. Wollenberg A.C. Stuart L.M. Stormo G.D. Irazoqui J.E. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.Immunity. 2014; 40: 896-909Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). This functional conservation of the TFEB/TFE3 pathway is further supported by a recent study showing that a bacterial membrane pore-forming toxin induces cellular autophagy in an HLH-30-dependent manner in C. elegans (Chen et al., 2017Chen H.D. Kao C.Y. Liu B.Y. Huang S.W. Kuo C.J. Ruan J.W. Lin Y.H. Huang C.R. Chen Y.H. Wang H.D. et al.HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans.Autophagy. 2017; 13: 371-385Crossref PubMed Scopus (31) Google Scholar). However, the mechanisms by which nematode and mammalian TFEB/TFE3 are activated during infection are still poorly understood. Recently, TFEB activation was found to involve phospholipase C and protein kinase D pathways both in C. elegans and mammals upon pathogen infection (Najibi et al., 2016Najibi M. Labed S.A. Visvikis O. Irazoqui J.E. An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense.Cell Rep. 2016; 15: 1728-1742Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Subsequent studies showed that lipopolysaccharide (LPS)-stimulated TFEB/TFE3 activation in murine macrophages induced cytokine production and secretion independent of mTORC1, but the specific pathway by which their activation was mediated was not elucidated (Pastore et al., 2016Pastore N. Brady O.A. Diab H.I. Martina J.A. Sun L. Huynh T. Lim J.A. Zare H. Raben N. Ballabio A. Puertollano R. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages.Autophagy. 2016; 12: 1240-1258Crossref PubMed Scopus (165) Google Scholar). Folliculin (FLCN) is a binding partner and negative regulator of 5′-AMP-activated protein kinase (AMPK) (Baba et al., 2006Baba M. Hong S.B. Sharma N. Warren M.B. Nickerson M.L. Iwamatsu A. Esposito D. Gillette W.K. Hopkins 3rd, R.F. Hartley J.L. et al.Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.Proc. Natl. Acad. Sci. USA. 2006; 103: 15552-15557Crossref PubMed Scopus (373) Google Scholar, Takagi et al., 2008Takagi Y. Kobayashi T. Shiono M. Wang L. Piao X. Sun G. Zhang D. Abe M. Hagiwara Y. Takahashi K. Hino O. Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein.Oncogene. 2008; 27: 5339-5347Crossref PubMed Scopus (106) Google Scholar), which was identified as a tumor suppressor protein responsible for the Birt-Hogg-Dubé (BHD) neoplastic syndrome in humans (Tee and Pause, 2013Tee A.R. Pause A. Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin.Fam. Cancer. 2013; 12: 367-372Crossref PubMed Scopus (10) Google Scholar). Importantly, the interaction of FLCN with AMPK is mediated by two homologous FLCN-binding proteins FNIP1 and FNIP2 (Baba et al., 2006Baba M. Hong S.B. Sharma N. Warren M.B. Nickerson M.L. Iwamatsu A. Esposito D. Gillette W.K. Hopkins 3rd, R.F. Hartley J.L. et al.Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.Proc. Natl. Acad. Sci. USA. 2006; 103: 15552-15557Crossref PubMed Scopus (373) Google Scholar, Takagi et al., 2008Takagi Y. Kobayashi T. Shiono M. Wang L. Piao X. Sun G. Zhang D. Abe M. Hagiwara Y. Takahashi K. Hino O. Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein.Oncogene. 2008; 27: 5339-5347Crossref PubMed Scopus (106) Google Scholar). Pathogenic mutations from BHD patients lead to a loss of FNIP/AMPK binding pointing to the functional significance of this interaction in tumor suppression (Baba et al., 2006Baba M. Hong S.B. Sharma N. Warren M.B. Nickerson M.L. Iwamatsu A. Esposito D. Gillette W.K. Hopkins 3rd, R.F. Hartley J.L. et al.Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.Proc. Natl. Acad. Sci. USA. 2006; 103: 15552-15557Crossref PubMed Scopus (373) Google Scholar). AMPK is a heterotrimeric enzyme, which monitors the energy status and maintains energy homeostasis under metabolic stress by activating catabolic processes and inhibiting anabolic pathways (Hardie, 2015Hardie D.G. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis.Curr. Opin. Cell Biol. 2015; 33: 1-7Crossref PubMed Scopus (344) Google Scholar, Hardie and Ashford, 2014Hardie D.G. Ashford M.L. AMPK: regulating energy balance at the cellular and whole body levels.Physiology (Bethesda). 2014; 29: 99-107Crossref PubMed Scopus (201) Google Scholar, Hardie et al., 2012Hardie D.G. Ross F.A. Hawley S.A. AMPK: a nutrient and energy sensor that maintains energy homeostasis.Nat. Rev. Mol. Cell Biol. 2012; 13: 251-262Crossref PubMed Scopus (2911) Google Scholar). We have previously shown that loss of FLCN or expression of a FLCN mutant unable to bind FNIP/AMPK led to chronic AMPK activation, resulting in increased ATP levels through an elevated glycolytic flux, oxidative phosphorylation, and autophagy (Possik et al., 2014Possik E. Jalali Z. Nouët Y. Yan M. Gingras M.C. Schmeisser K. Panaite L. Dupuy F. Kharitidi D. Chotard L. et al.Folliculin regulates ampk-dependent autophagy and metabolic stress survival.PLoS Genet. 2014; 10: e1004273Crossref PubMed Scopus (82) Google Scholar, Possik et al., 2015Possik E. Ajisebutu A. Manteghi S. Gingras M.C. Vijayaraghavan T. Flamand M. Coull B. Schmeisser K. Duchaine T. van Steensel M. et al.FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.PLoS Genet. 2015; 11: e1005520Crossref PubMed Scopus (33) Google Scholar, Possik and Pause, 2016Possik E. Pause A. Glycogen: A must have storage to survive stressful emergencies.Worm. 2016; 5: e1156831Crossref PubMed Google Scholar). Importantly, we have shown that loss of FLCN mediates resistance to oxidative stress, heat, anoxia, obesity, and hyperosmotic stresses via AMPK activation in C. elegans and mammalian models (Possik et al., 2014Possik E. Jalali Z. Nouët Y. Yan M. Gingras M.C. Schmeisser K. Panaite L. Dupuy F. Kharitidi D. Chotard L. et al.Folliculin regulates ampk-dependent autophagy and metabolic stress survival.PLoS Genet. 2014; 10: e1004273Crossref PubMed Scopus (82) Google Scholar, Possik et al., 2015Possik E. Ajisebutu A. Manteghi S. Gingras M.C. Vijayaraghavan T. Flamand M. Coull B. Schmeisser K. Duchaine T. van Steensel M. et al.FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.PLoS Genet. 2015; 11: e1005520Crossref PubMed Scopus (33) Google Scholar, Possik and Pause, 2016Possik E. Pause A. Glycogen: A must have storage to survive stressful emergencies.Worm. 2016; 5: e1156831Crossref PubMed Google Scholar, Yan et al., 2014Yan M. Gingras M.C. Dunlop E.A. Nouët Y. Dupuy F. Jalali Z. Possik E. Coull B.J. Kharitidi D. Dydensborg A.B. et al.The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation.J. Clin. Invest. 2014; 124: 2640-2650Crossref PubMed Scopus (101) Google Scholar). Although a role for FLCN in regulating immune responses has not been reported, the functional role for AMPK in innate immunity seems to be context and cell type dependent (Blagih et al., 2015Blagih J. Coulombe F. Vincent E.E. Dupuy F. Galicia-Vázquez G. Yurchenko E. Raissi T.C. van der Windt G.J. Viollet B. Pearce E.L. et al.The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo.Immunity. 2015; 42: 41-54Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, Prantner et al., 2017Prantner D. Perkins D.J. Vogel S.N. AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling.J. Biol. Chem. 2017; 292: 292-304Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In this study, we demonstrate an evolutionarily conserved pathogen-resistance mechanism mediated by FLCN and AMPK via TFEB/TFE3. Specifically, we show that loss of flcn-1 in C. elegans, which leads to chronic AMPK activation, enhances the HLH-30 nuclear translocation and induces the expression of hlh-30-dependent antimicrobial genes upon infection, mediating resistance to bacterial pathogens. Using RNA sequencing (RNA-seq), we show that many hlh-30-dependent antimicrobial genes are regulated by AMPK upon S. aureus infection. AMPK loss reduces HLH-30 nuclear translocation and abrogates the increased resistance of flcn-1(ok975) mutant animals to pathogens. Furthermore, we show that constitutive activation of AMPK C. elegans nematodes leads to an HLH-30-dependent increase in pathogen resistance, similar to what we observe upon loss of flcn-1. Importantly, we show that this pathway of regulation is evolutionarily conserved, and that FLCN and AMPK regulate TFEB/TFE3-driven cytokine and inflammatory genes in mouse embryonic fibroblasts and macrophages. Overall, our data suggest an essential role of the FLCN/AMPK axis in the regulation of host defense response via TFEB/TFE3, highlighting a possible mechanism likely to contribute to tumor formation in BHD patients. Our findings also shed light on the potential use of AMPK activators in the stimulation of the innate immune response and defense against pathogens. To understand the physiological role of FLCN-1, we compared gene expression profiles of wild-type and flcn-1(ok975) mutant animals. Among differentially expressed genes, 243 transcripts were upregulated in flcn-1(ok975) mutant animals compared with wild-type animals at basal level (Table S3, sheet 1) and were classified based on their biological functions (Table 1; Table S3, sheets 1 and 2). Genes associated with stress response, innate immune response, defense mechanisms, and response to stimulus processes, including heat shock proteins, C-type lectins, lysozymes, and cytochrome P450 genes, were induced in flcn-1(ok975) unstressed mutant animals compared with wild-type animals (Table 1; Table S1, sheet 3; Figure 1A). Selected genes were validated using qRT-PCR (Figure 1B; Table S3, sheet 3). On the other hand, 704 genes were shown to be downregulated in flcn-1(ok975) mutant animals (Table S3, sheet 4) and are involved in various processes that control proliferation and growth (Table S3, sheet 5). These results indicate that a differential gene expression might be providing advantage to the flcn-1 mutant worms prior to stress or pathogen attacks. This is in accordance with our previously reported results where loss of flcn-1(ok975) conferred resistance to oxidative stress, heat stress, anoxia, and hyperosmotic stress in C. elegans (Possik et al., 2014Possik E. Jalali Z. Nouët Y. Yan M. Gingras M.C. Schmeisser K. Panaite L. Dupuy F. Kharitidi D. Chotard L. et al.Folliculin regulates ampk-dependent autophagy and metabolic stress survival.PLoS Genet. 2014; 10: e1004273Crossref PubMed Scopus (82) Google Scholar, Possik et al., 2015Possik E. Ajisebutu A. Manteghi S. Gingras M.C. Vijayaraghavan T. Flamand M. Coull B. Schmeisser K. Duchaine T. van Steensel M. et al.FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.PLoS Genet. 2015; 11: e1005520Crossref PubMed Scopus (33) Google Scholar, Possik and Pause, 2015Possik E. Pause A. Measuring oxidative stress resistance of Caenorhabditis elegans in 96-well microtiter plates.J. Vis. Exp. 2015; 99: e52746Google Scholar, Possik and Pause, 2016Possik E. Pause A. Glycogen: A must have storage to survive stressful emergencies.Worm. 2016; 5: e1156831Crossref PubMed Google Scholar, Yan et al., 2014Yan M. Gingras M.C. Dunlop E.A. Nouët Y. Dupuy F. Jalali Z. Possik E. Coull B.J. Kharitidi D. Dydensborg A.B. et al.The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation.J. Clin. Invest. 2014; 124: 2640-2650Crossref PubMed Scopus (101) Google Scholar). Because it was demonstrated that the osmo-sensitive gene expression mimics the transcriptional profiles of pathogen infection (Rohlfing et al., 2010Rohlfing A.K. Miteva Y. Hannenhalli S. Lamitina T. Genetic and physiological activation of osmosensitive gene expression mimics transcriptional signatures of pathogen infection in C. elegans.PLoS ONE. 2010; 5: e9010Crossref PubMed Scopus (54) Google Scholar), we compared the overlap between genes upregulated in flcn-1(ok975) mutant animals and genes induced by infection of C. elegans nematodes with pathogens (Irazoqui et al., 2010aIrazoqui J.E. Troemel E.R. Feinbaum R.L. Luhachack L.G. Cezairliyan B.O. Ausubel F.M. Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus.PLoS Pathog. 2010; 6: e1000982Crossref PubMed Scopus (229) Google Scholar, Troemel et al., 2006Troemel E.R. Chu S.W. Reinke V. Lee S.S. Ausubel F.M. Kim D.H. p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.PLoS Genet. 2006; 2: e183Crossref PubMed Scopus (446) Google Scholar). Indeed, we found a significant overlap of the transcriptome especially upon Staphylococcus aureus (S. aureus) (Figure S1A; Table S3, sheet 6) and Pseudomonas aeruginosa (P. aeruginosa) infection (Figure S1B; Table S3, sheet 7).Table 1Genes Classified according to Family Functions and Upregulated in flcn-1(ok975) Mutant AnimalsGene IDGeneDescriptionFold Changep ValueC-Type LectinsH16D19.1clec-13C-type lectin8.777.37E−7T20B3.8clec-23C-type lectin3.008.39E−4F49A5.4clec-24C-type lectin2.322.99E−3T20B3.16clec-36C-type lectin1.692.19E−3T20B3.13clec-40C-type lectin2.683.41E−4ZK666.6clec-60C-type lectin3.107.05E−4ZK666.7clec-61C-type lectin2.672.21E−3F35C5.6.2clec-63C-type lectin1.427.74E−4F35C5.8.1clec-65C-type lectin1.361.00E−3Y46C8L.8clec-74C-type lectin3.483.16E−3Y45G2A.8aclec-82C-type lectin2.041.07E−3C54D1.2clec-86C-type lectin1.799.79E−3Y54G2A.6clec-85C-type lectin1.591.05E−4R13F6.2clec-159C-type lectin2.562.79E−3F38A1.5clec-166C-type lectin1.628.68E−4F59A7.5clec-206C-type lectin2.361.35E−3F38A5.3alec-11galectin1.642.87E−4Heat Shock Protein FamilyT27E4.8hsp-16.1heat shock protein1.761.65E−5Y46H3A.3hsp-16.2heat shock protein2.831.01E−5Y46H3A.2hsp-16.41heat shock protein3.395.58E−7T27E4.3hsp-16.48heat shock protein1.811.01E−5Cytochrome P450 FamilyT10B9.1cyp-13A4cytochrome P450 family2.301.43E−3T10B9.2cyp-13A5cytochrome P450 family2.104.59E−4K09A11.3cyp-14A2cytochrome P450 family1.601.24E−3C36A4.1cyp-25A1cytochrome P450 family1.885.18E−4B0213.14cyp-34A8cytochrome P450 family1.481.73E−3B0213.15bcyp-34A9cytochrome P450 family1.612.95E−3C03G6.15cyp-35A2cytochrome P450 family1.817.40E−6K09D9.2cyp-35A3cytochrome P450 family1.924.18E−5C49G7.8cyp-35A4cytochrome P450 family2.041.06E−4Lysosome FamilyY22F5A.5lys-2lysosome1.401.08E−3Y22F5A.6lys-3lysosome6.156.96E−3C02A12.4lys-7lysosome2.545.96E−3F17E9.11lys-10lysosome3.083.72E−4Serpentine ReceptorY105C5B.10srv-16serpentine receptor, class V2.253.08E−3C01B4.5srd-61serpentine receptor, class D2.301.81E−3F36G9.5sru-22serpentine receptor, class U2.333.23E−4F36G9.6sru-23serpentine receptor, class U2.651.89E−4C25E10.3Bsrsx-34serpentine receptor, class SX2.817.37E−4R52.7srh-195serpentine receptor, class H2.982.80E−3K12D9.5srw-120serpentine receptor, class W3.032.07E−4T25E12.13srz-99serpentine receptor, class Z2.351.71E−3T25E12.11srz-100serpentine receptor, class Z3.581.56E−4K12D9.7srw-119serpentine receptor, class W5.522.33E−7C13D9.1srr-6serpentine receptor, class R5.754.95E−6F-box FamilyK05F6.1FBXB-49F-box B protein2.281.27E−3F10A3.3FBXA-18F-box A protein2.141.79E−3C08E3.10AFBXA-158F-box A protein5.038.97E−6F42G2.4FBXA-182F-box A protein1.842.77E−3Thaumatin FamilyF28D1.3thn-1thaumatin family2.377.83E−8F28D1.5thn-2thaumatin family2.732.16E−11Tetraspanin FamilyC02F5.8TSP-1tetraspanin family4.113.71E−6C02F5.11TSP-2tetraspanin family3.571.65E−5Arrestin Domain FamilyF48F7.7ARRD-24arrestin domain protein7.762.87E−4Y17G7B.14ARRD-8arrestin domain protein3.962.65E−4M176.1ARRD-3arrestin domain protein3.534.90E−4 Open table in a new tab Next, we asked whether flcn-1(ok975) mutant animals display enhanced resistance to pathogens. Strikingly, we found that the flcn-1(ok975) mutant animals are more resistant than wild-type animals to S. aureus and P. aeruginosa infection (Figures 1C and 1D; Table S1). These phenotypes were rescued using a transgenic flcn-1 mutant animal re-expressing flcn-1 (Figure 1E; Table S1). These results demonstrate an important role for flcn-1 in the induction of antimicrobial peptides and stress response genes mediating the resistance to infection with bacterial pathogens. HLH-30, the worm ortholog of TFEB/TFE3, has been reported to modulate longevity and pathogen resistance in C. elegans through activation of autophagy and expression of antimicrobial genes (Lapierre et al., 2013Lapierre L.R. De Magalhaes Filho C.D. McQuary P.R. Chu C.C. Visvikis O. Chang J.T. Gelino S. Ong B. Davis A.E. Irazoqui J.E. et al.The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans.Nat. Commun. 2013; 4: 2267Crossref PubMed Scopus (303) Google Scholar, Settembre et al., 2013Settembre C. De Cegli R. Mansueto G. Saha P.K. Vetrini F. Visvikis O. Huynh T. Carissimo A. Palmer D. Klisch T.J. et al.TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.Nat. Cell Biol. 2013; 15" @default.
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• W2900253406 title "The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance" @default.
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