Neuronal HLH-30/TFEB modulates muscle mitochondrial fragmentation to improve thermoresistance in C. elegans
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE200383 | GEO | 2022/12/31
REPOSITORIES: GEO
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Project description:Transcription factor EB (TFEB) is a conserved master transcriptional activator of autophagy and lysosomal genes that modulates organismal lifespan regulation and stress resistance. As neurons can coordinate organism-wide processes, we investigated the role of neuronal TFEB in stress resistance and longevity. To this end, the Caenorhabditis elegans TFEB ortholog, hlh-30, was rescued panneuronally in hlh-30 loss of function mutants. While important in the long lifespan of daf-2 animals, neuronal HLH-30/TFEB was not sufficient to restore normal lifespan in short-lived hlh-30 mutants. However, neuronal HLH-30/TFEB rescue mediated robust improvements in the heat stress resistance of wildtype but not daf-2 animals. Notably, these mechanisms can be uncoupled, as neuronal HLH-30/TFEB requires DAF-16/FOXO to regulate longevity but not thermoresistance. Through further transcriptomics profiling and functional analysis, we discovered that neuronal HLH-30/TFEB modulates neurotransmission through the hitherto uncharacterized protein W06A11.1 by inducing peripheral mitochondrial fragmentation and organismal heat stress resistance in a non-cell autonomous manner. Taken together, this study uncovers a novel mechanism of heat stress protection mediated by neuronal HLH-30/TFEB.
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Project description:Neuronal HLH-30/TFEB modulates muscle mitochondrial fragmentation to improve thermoresistance in C. elegans
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Project description:Autophagy is a cellular recycling process that has an important anti-aging role, but the underlying molecular mechanism is not well understood. The mammalian transcription factor EB (TFEB) was recently shown to regulate multiple genes in the autophagy process. Here we show that the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans and, in addition, has a key role in lifespan determination. We demonstrate that hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan. Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models and, notably, nuclear TFEB levels are augmented in the livers of mice subjected to dietary restriction, a known longevity-extending regimen. Collectively, our results demonstrate a conserved role for HLH-30 and TFEB in autophagy, and possibly longevity, and identify HLH-30 as a uniquely important transcription factor for lifespan modulation in Caenorhabditis elegans.
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Project description: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.
2024-08-22 | GSE245430 | GEO
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
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
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
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
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
Project description:Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a polyglutamine expansion disease arising from a trinucleotide CAG repeat expansion in exon 10 of the gene ATXN3. There are no effective pharmacological treatments for MJD, thus the identification of new pathogenic mechanisms, and the development of novel therapeutics is urgently needed. In this study, we performed a comprehensive, blind drug screen of 3942 compounds (many FDA approved) and identified small molecules that rescued the motor-deficient phenotype in transgenic ATXN3 Caenorhabditis elegans strain. Out of this screen, five lead compounds restoring motility, protecting against neurodegeneration, and increasing the lifespan in ATXN3-CAG89 mutant worms were identified. These compounds were alfacalcidol, chenodiol, cyclophosphamide, fenbufen, and sulfaphenazole. We then investigated how these molecules might exert their neuroprotective properties. We found that three of these compounds, chenodiol, fenbufen, and sulfaphenazole, act as modulators for TFEB/HLH-30, a key transcriptional regulator of the autophagy process, and require this gene for their neuroprotective activities. These genetic-chemical approaches, using genetic C. elegans models for MJD and the screening, are promising tools to understand the mechanisms and pathways causing neurodegeneration, leading to MJD. Positively acting compounds may be promising candidates for investigation in mammalian models of MJD and preclinical applications in the treatment of this disease.
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