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HLH-30/TFEB-regulated autophagy mediates sexual dimorphism in immunity in Caenorhabditis elegans

ABSTRACT: Sexual dimorphism affects diverse biological functions such as immune responses. However, mechanisms by which different sexes alter immunity remained largely unknown. By using Caenorhabditis elegans as a model, here we show that male animals exhibit enhanced immunity against various pathogenic bacteria via upregulating autophagy. We found that male C. elegans displayed upregulation of helix loop helix 30 (HLH-30)/transcription factor EB (TFEB), a transcription factor crucial for autophagy, which contributed to the enhanced anti-bacterial immunity. We showed that autophagy-related protein 2 (atg-2) that is upregulated by HLH-30/TFEB, mediated increased immunity in male animals. Thus, male C. elegans appear to be equipped with enhanced autophagy for increasing pathogen resistance, likely conferring prolonged mate search with less infection.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE245430 | GEO | 2024/08/22

REPOSITORIES: GEO

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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 in C. elegans

Project description:Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate tolerance to bacterial infection, but less is known about the bona fide bacterial effector that activates HLH-30 and autophagy. Here, we unveil that bacterial membrane pore-forming toxin (PFT) induces autophagy through an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C. elegans. These results demonstrate that autophagic pathways and autophagy are induced partly at the transcriptional level through HLH-30 activation and are required to protect metazoan upon PFT intoxication. Together, our data show a new and powerful connection between HLH-30-mediated autophagy and epithelium intrinsic cellular defense against the single most common mode of bacterial attack in vivo.

2016-11-01 | GSE78878 | GEO

Comparison of gene expression between wild type (N2) and hlh-30(tm1978) mutant worms

2009-07-24 | GSE15762 | GEO

A conserved cysteine-based redox mechanism sustains TFEB/HLH-30 activity under persistent stress

Project description:Mammalian TFEB and TFE3, as well as their ortholog in C. elegans HLH-30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress and pathogen infection. In this study we identify a novel mechanism of TFEB/HLH-30 regulation through a cysteine-mediated redox switch. Under stress conditions, TFEB-C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1-mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH-30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility. Therefore, cysteine oxidation represents a new type of TFEB post-translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH-30 target genes.

2021-01-22 | PXD022258 | Pride

Transcription profiling of C. elegans wild type (N2) and hlh-30(tm1978) mutants

Project description:The hlh-30 gene encodes a C. elegans basic-helix-loop-helix (bHLH) transcription factor; We compared RNA from wild type worms and worms mutant for the hlh-30 gene to identify putative target genes of the HLH-30 transcription factor. Experiment Overall Design: Total RNA from three biological replicates were isolated from embryos, L1 larvae, and L2 larvae from both wild type and hlh-30(tm1978) mutant worms

2009-08-07 | E-GEOD-15762 | biostudies-arrayexpress

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Project description:Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

2024-02-07 | MTBLS6847 | MetaboLights

RNA seq to determine differential gene expression in pgph-2 oe C.elegans animals and the subset of HLH-30-dependent genes on normal growth and excess glucose conditions.

Project description:Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly-discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. We demonstrated that G3PP (PGPH-2) overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and is an attractive target for age-related metabolic disorders linked to excess nutrients. This transcriptomics analysis was designed to determine genes that are differentially regulated in pgph-2 oe animals in comparison to wild-type animals on normal and excess glucose conditions. To determine the role of HLH-30 in the regulation of gene expression, we also used pgph-2 oe; hlh-30 and hlh-30 mutant animals and found a signature mediated by pgph-2 oe and HLH-30-dependent.

2023-04-30 | GSE228784 | GEO

HLH-30/TFEB is a master regulator of reproductive quiescence

Project description:All animals have evolved the ability to survive nutrient deprivation, and nutrient signaling pathways are conserved modulators of health and disease. In C. elegans, late-larval starvation provokes adult reproductive diapause (ARD), a long-lived quiescent state that enables animals to survive months without food, yet underlying molecular mechanisms remain unknown. Here, we show that ARD is distinct from other forms of diapause, and shows surprisingly little requirement for canonical longevity pathways, autophagy and fat metabolism. Instead ARD depends dramatically on HLH-30/TFEB transcription factor to promote morphologic and metabolic remodeling involved in ARD entry, survival, and recovery, suggesting it is a master regulator of reproductive quiescence. TFEB transcriptome and genetic analyses reveal that Max-like HLH factors, mTOR, AMP-kinase, protein synthesis, and mitochondrial fusion are target processes that promote ARD longevity. Evidently reproductive quiescence rewires metabolism in unique ways to ensure long-term survival, and could illuminate similar mechanisms acting in latent tumorigenesis, and long-term fasting.

2020-03-30 | GSE126632 | GEO

Neuronal HLH-30 regulates glp-1 longevity independent of neuronal MML-1/MXL-2

Project description:Accumulating evidence has demonstrated the presence of inter-tissue communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix-loop-helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germline-less Caenorhabditis elegans. However, it is unknown what tissues these factors target to promote longevity. Here, using tissue-specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germline-less animals. Neuronal functions of MML-1/MXL-2 and HLH-30 are also essential to prevent aging in non-neuronal tissues, including muscle and the intestine. Interestingly, however, both the temporal requirement and the downstream function of MML-1 in neurons were distinct from those of HLH-30. MML-1 was active early, while HLH-30 functioned later in life to sustain longevity in germline-less animals. Moreover, neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a novel downstream target of MML-1 but not HLH-30. Furthermore, the MML-1–GTL-5 axis in neurons is critical to prevent an age-dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a novel molecular network involving neuronal MML-1 function in both neural and peripheral tissues.

2023-09-18 | GSE234429 | GEO

PRMT-7/PRMT7 activates HLH-30/TFEB to guard plasma membrane integrity compromised by pore-forming toxins

Project description:This research reveals that protein arginine methyltransferase-7 (PRMT-7) is indispensable to the nuclear transactivation of HLH-30. We demonstrated that PRMT-7 participates in the methylation of HLH-30 on its Rag complex binding domain to facilitate its nuclear localization. Moreover, we showed that PRMT7 is evolutionarily conserved to regulate TFEB cellular localization and repair plasma damage caused by PFTs in human intestinal cells.

2024-01-26 | PXD043101 | Pride

A cascade for zinc mediated transcriptional activation by the zinc-sensing nuclear receptor HIZR-1 on the regulator of lysosome biogenesis HLH-30 to achieve homeostasis

Project description:Zinc is an essential element for animals and stored in de novo synthesized lysosome related organelles called bilobed granules in Caenorhabditis elegans. Defining how zinc regulated transcription drives the observed lysosome remodeling is key to understand zinc homeostasis processes. Here we describe a positively regulated zinc network controlled by HIZR-1 and HLH-30, the zinc sensor and the master regulator of the autophagy-lysosomal pathway in Caenorhabditis elegans, respectively; essential for connecting zinc homeostasis to lysosome biogenesis. Our studies indicate that either hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome-genes under high dietary zinc conditions. Consistent with the hizr-1 and hlh-30 dependency for high zinc response, we found DNA enhancer elements corresponding to the high zinc activation element consistently adjacent to E-boxes in the promoter regions of lysosome-genes. We defined a regulatory network based on the contribution of each transcription factor. Since zinc cannot be degraded, the autophagy-lysosomal pathway could play a key role in removing zinc excess

2021-05-15 | GSE172079 | GEO

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