HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in<i>C. elegans</i>

Chen, Huan Da; Kao, Cheng–Yuan; Liu, Bang Yu; Huang, Shin Whei; Kuo, Chengi; Ruan, Jhen-Wei; Lin, Yen Hung; Huang, Cheng; Chen, Yu-Hung; Wang, Horng-Dar; Aroian, Raffi V.; Chen, Chang Shi

doi:10.1080/15548627.2016.1256933

Cited by 45 publications

(49 citation statements)

References 59 publications

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“…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 [6, 18, 19]. This functional conservation of the TFEB/TFE3 pathway is further supported by a recent study showing that bacterial membrane pore-forming toxin induces cellular autophagy in an HLH-30-dependent manner in C. elegans [20]. However, the mechanisms by which nematode and mammalian TFEB/TFE3 are activated during infection are still poorly understood.…”

Section: Introductionmentioning

confidence: 86%

The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

El–Houjeiri

Possik

Vijayaraghavan

et al. 2018

Preprint

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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'-AMPactivated 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. translocation ( Figure 3E). These findings suggest that loss of FLCN drives HLH-30/TFEB/TFE3

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Section: Introductionmentioning

confidence: 86%

The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

El–Houjeiri

Possik

Vijayaraghavan

et al. 2018

Preprint

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“…A recent report showed that the PFTs Cry5B and Cry21A, produced by the extracellular Gram-positive bacterium Bacillus thuringiensis, induce autophagy in C. elegans via TFEB/HLH-30. 44 Specifically, C. elegans fed with E. coli expressing Cry5B were examined by electron microscopy and by fluorescence microscopy to detect autophagy marker proteins. Cry5B feeding not only increased the abundance of autophagic vesicles but also induced the nuclear translocation of HLH-30::GFP in intestinal cells.…”

Section: Hlh-30/tfeb and Tolerance Of C Elegans To Infectionmentioning

confidence: 99%

“…Interestingly, transcriptomic analysis of the Cry5B-fed C. elegans revealed that HLH-30/TFEB also regulates the transcription of membrane-repair genes (e.g., the small GTPase rab-5). Autophagy genes are required for the repair of membrane pores induced by Cry5B, 44 suggesting an additional function for autophagy in host defense to PFT-producing bacteria. Among the genes induced by Cry5B are a number related to C-type lectins, lysosomes, peroxisomes, and heat shock proteins, which is in agreement with the overall function of TFEB/HLH-30 in regulating expression of cytoprotective and antimicrobial genes in defense against S. aureus infection.…”

Section: Hlh-30/tfeb and Tolerance Of C Elegans To Infectionmentioning

confidence: 99%

“…1). Several conserved autophagy-related (Atg) proteins, many of which have clear homologs in C. elegans and D. melanogaster (Table 1), 34,40,41,44,45 S. enterica, P. aeruginosa, N. parisii, Cry5B lgg-2 MAP1LC3 S. aureus 41 sqst-1 SQSTM1 N. parisii 40 Autophagy-related genes with reported roles in anti-viral, -bacterial, and -fungal immunity in D. melanogaster and C. elegans are shown, together with the yeast/human homologs. VSV, vesicular stomatitis virus; Cry5B, pore-forming toxin from B. thuringiensis.…”

Section: Introduction To Autophagymentioning

confidence: 99%

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Autophagy and innate immunity: Insights from invertebrate model organisms

2018

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Macroautophagy/autophagy is a fundamental intracellular degradation process with multiple roles in immunity, including direct elimination of intracellular microorganisms via 'xenophagy.' In this review, we summarize studies from the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans that highlight the roles of autophagy in innate immune responses to viral, bacterial, and fungal pathogens. Research from these genetically tractable invertebrates has uncovered several conserved immunological paradigms, such as direct targeting of intracellular pathogens by xenophagy and regulation of autophagy by pattern recognition receptors in D. melanogaster. Although C. elegans has no known pattern recognition receptors, this organism has been particularly useful in understanding many aspects of innate immunity. Indeed, work in C. elegans was the first to show xenophagic targeting of microsporidia, a fungal pathogen that infects all animals, and to identify TFEB/HLH-30, a helix-loop-helix transcription factor, as an evolutionarily conserved regulator of autophagy gene expression and host tolerance. Studies in C. elegans have also highlighted the more recently appreciated relationship between autophagy and tolerance to extracellular pathogens. Studies of simple, short-lived invertebrates such as flies and worms will continue to provide valuable insights into the molecular mechanisms by which autophagy and immunity pathways intersect and their contribution to organismal survival. Abbreviations Atg autophagy related BECN1 Beclin 1 CALCOCO2 calcium binding and coiled-coil domain 2 Cry5B crystal toxin 5B Daf abnormal dauer formation DKF-1 D kinase family-1 EPG-7 Ectopic P Granules-7 FuDR fluorodeoxyuridine GFP green fluorescent protein HLH-30 Helix Loop Helix-30 Imd immune deficiency ins-18 INSulin related-18; LET-363, LEThal-363 lgg-1 LC3, GABARAP and GATE-16 family-1 MAPK mitogen-activated protein kinase MATH the meprin and TRAF homology MTOR mechanistic target of rapamycin NBR1 neighbor of BRCA1 gene 1 NFKB nuclear factor of kappa light polypeptide gene enhancer in B cells NOD nucleotide-binding oligomerization domain containing OPTN optineurin PAMPs pathogen-associated molecular patterns Park2 Parkinson disease (autosomal recessive, juvenile) 2, parkin pdr-1 Parkinson disease related PFTs pore-forming toxins PGRP peptidoglycan-recognition proteins PIK3C3 phosphatidylinositol 3- kinase catalytic subunit type 3 pink-1 PINK (PTEN-I induced kinase) homolog PRKD protein kinase D; PLC, phospholipase C PRKN parkin RBR E3 ubiquitin protein ligase PRRs pattern-recognition receptors PtdIns3P phosphatidylinositol-3-phosphate rab-5 RAB family-5 RB1CC1 RB1-inducible coiled-coil 1 RNAi RNA interference sqst SeQueSTosome related SQSTM1 sequestosome 1 TBK1 TANK-binding kinase 1 TFEB transcription factor EB TGFB/TGF-β transforming growth factor beta TLRs toll-like receptors unc-51 UNCoordinated-51 VPS vacuolar protein sorting; VSV, vesicular stomatitis virus VSV-G VSV surface glycoprotein G Wipi2 WD repeat domain, phosphoin...

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“…Recent reports suggested that Rab5 was significantly abolished in the hlh‐30 (ortholog of TFEB in mammals) mutant C. elegans compare with wild‐type strain . In squamous cell carcinomas, TFEB knockdown induces an enlargement of EEA1 labeled endosomes .…”

Section: Discussionmentioning

confidence: 99%

Pseudoginsenoside‐F11 alleviates oligomeric β‐amyloid‐induced endosome‐lysosome defects in microglia

Yao

Xue

Zhang

et al. 2018

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Amyloid accumulation in the brain is the major pathological hallmark of Alzheimer disease (AD).Amyloid beta (Aβ) is cleared by the endosomal-autophagy-lysosomal system, which is impaired in AD pathogenesis by an unknown mechanism. Pseudoginsenoside-F11 (PF11), an ocotilloltype ginsenoside, has been demonstrated to decrease the level of Aβ in APP/PS1 mouse brain and to protect neurons by inhibiting the activation of microglia in vitro. The present study showed that PF11 was capable of increasing the uptake and degradation of oligomeric Aβ in cultured microglia. Oligomeric Aβ (oAβ) interrupted the autophagy-lysosomal degradative system by regulating the nuclear translocation of transcription factor EB (TFEB), a master factor in lysosomal biogenesis. Conversion of Rab5 to Rab7, which is important for the mechanism of cargo progression from early to late endosomes, was also interrupted by high-concentration oAβ.Notably, in the PF11-treated microglial cells, a dramatic increase of the lysosome-associated proteins and enzyme expression were observed, along with the intracellular pH steady state, indicating the improvement of lysosomal function. In addition, PF11 induced TFEB nuclear translocation in microglia treated with high-concentration oAβ. Furthermore, PF11 was able to restore Rab conversion, suggesting an effective role of PF11 in the maturation of endosomes.These data provide evidence that PF11 can reverse the dysfunction of the endosomal-lysosomal system induced by high-concentration oAβ in microglia, and this might be the main mechanism by which PF11 facilitates oAβ clearance. Accordingly, we propose that PF11 should be considered as a potential agent for treating AD. K E Y W O R D S endocytosis, lysosomal function, oligomeric Aβ, pseudoginsenoside-F11

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HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin inC. elegans

Cited by 45 publications

References 59 publications

The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

Autophagy and innate immunity: Insights from invertebrate model organisms

Pseudoginsenoside‐F11 alleviates oligomeric β‐amyloid‐induced endosome‐lysosome defects in microglia

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