MML-1/Mondo complexes regulate HLH-30/TFEB via TOR inhibition to promote longevity in response to signals from the reproductive system
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Caenorhabditis elegans
SUBMITTER: Sven Templer
PROVIDER: E-MTAB-3686 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival.
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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: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: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:RNA-seq performed for studying transcriptomic changesmodulated by neuronal HLH-30 during heat stress
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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: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: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:MML-1/Mondo complexes regulate HLH-30/TFEB via TOR inhibition to promote longevity in response to signals from the reproductive system
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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