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The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) is known for protecting dopaminergic neurons and functioning in various other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants exhibit defects such as increased endoplasmic reticulum (ER) stress, dopaminergic neurodegeneration, and abnormal protein aggregation. These findings suggest an essential role for MANF in cellular processes. However, the mechanisms by which intracellular and extracellular MANF regulate broader cellular functions remain unclear. We report a unique mechanism of action for MANF-1 that involves the transcription factor HLH-30/TFEB-mediated signaling to regulate autophagy and lysosomal function. Multiple transgenic strains overexpressing MANF-1 showed extended lifespan of animals, reduced protein aggregation, and improved neuronal survival. Using fluorescently tagged MANF-1, we observed tissue-specific localization of the protein, which was dependent on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes and utilizes the endosomal pathway. Consistent with the lysosomal localization, our transcriptomic study of MANF-1 and analyses of autophagy regulators demonstrated that MANF-1 promotes proteostasis by regulating autophagic flux and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of stress response, proteostasis, and aging.
Pubmed ID: 39418305
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View all literature mentionsCenter that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.
View all literature mentionsCaenorhabditis elegans with name zcIs4 V. from WB.
View all literature mentionsCaenorhabditis elegans with name hjIs14. from WB.
View all literature mentionsCaenorhabditis elegans with name bIs34. from WB.
View all literature mentionsCaenorhabditis elegans with name sqIs13. from WB.
View all literature mentionsCaenorhabditis elegans with name otIs45 V. from WB.
View all literature mentionsCaenorhabditis elegans with name sqIs17. from WB.
View all literature mentionsCaenorhabditis elegans with name rmIs132 [unc-54p::Q35::YFP] from WB.
View all literature mentionsCentral data repository for nematode biology including complete genomic sequence, gene predictions and orthology assignments from range of related nematodes.Data concerning genetics, genomics and biology of C. elegans and related nematodes. Derived from initial ACeDB database of C. elegans genetic and sequence information, WormBase includes genomic, anatomical and functional information of C. elegans, other Caenorhabditis species and other nematodes. Maintains public FTP site where researchers can find many commonly requested files and datasets, WormBase software and prepackaged databases.
View all literature mentionsCaenorhabditis elegans with name pkIs2386 [unc-54p::alpha-synnuclein::YFP + unc-119(+)] from WB.
View all literature mentionsCaenorhabditis elegans with name sqIs11. from WB.
View all literature mentionsCaenorhabditis elegans with name hlh-30(tm1978) IV. from WB.
View all literature mentionsCaenorhabditis elegans with name unc-119(ed3) III; pwIs50. from WB.
View all literature mentionsCaenorhabditis elegans with name zcIs14. from WB.
View all literature mentionsCaenorhabditis elegans with name rmIs133 [unc-54p::Q40::YFP]X from WB.
View all literature mentionsCaenorhabditis elegans with name unc-119(ed3) III; cdIs54. from WB.
View all literature mentionsCaenorhabditis elegans with name Caenorhabditis elegans wild isolate. from WB.
View all literature mentionsCaenorhabditis elegans with name ldrIs1. from WB.
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