Regulators of Lysosome Function and Dynamics in<i>Caenorhabditis elegans</i>

Gee, Kevin; Zamora, Danniel; Horm, Teresa M.; George, Laeth; Upchurch, Cameron; Randall, Justin R.; Weaver, Colby; Sanford, Caitlin Frances; Miller, Austin; Hernandez, Sebastian; Dang, Hope; Fares, Hanna

doi:10.1534/g3.116.037515

Cited by 7 publications

(4 citation statements)

References 61 publications

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“…However, there is still no direct evidence of lysosomal storage in any organism. Mutating clh-6 in nematodes dramatically alters resting lysosomal chloride within 1 day of adulthood and impairs the ability of the lysosome to degrade cargo. , Interestingly, we observe normal lysosomal viscosity at these early time points in clh-6 , likely indicating that stored material has not yet built up. Importantly, at increasing times of 24 h, 48 and 72 h, lysosomal viscosity also increased steadily, directly reflecting the consequences of accumulated material.…”

Section: Measurement Of Lysosomal Viscosity In Cell Culturementioning

confidence: 66%

“…To see if lysosomal viscosity could report more generally on different types of accumulated material in the lysosome, we investigated a selection of LSD models in the model organism Caenorhabditis elegans . C. elegans homologues of proteins responsible for most human LSDs have been identified and studied. , These models recapitulate many features of mammalian models including changes in lysosomal pH, morphology, degradative capacity, and dysregulated autophagy. ,− The short lifespan, ease of handling, and compatibility with microfluidic technologies also make C. elegans amenable to high-throughput screening methods . Furthermore, one can leverage versatile genetics of C. elegans to dissect the mechanisms of action of various therapeutics …”

Section: Measurement Of Lysosomal Viscosity In Cell Culturementioning

confidence: 99%

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Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases

2018

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We describe a new method to measure viscosity within subcellular organelles of a living cell using nanorheology. We demonstrate proof of concept by measuring viscosity in lysosomes in multiple cell types and disease models. The lysosome is an organelle responsible for the breakdown of complex biomolecules. When different lysosomal proteins are defective, they are unable to break down specific biological substrates, which get stored within the lysosome, causing about 70 fatal diseases called lysosomal storage disorders (LSDs). Although the buildup of storage material is critical to the pathology of these diseases, methods to monitor cargo accumulation in the lysosome are lacking for most LSDs. Using passive particle tracking nanorheology and fluorescence recovery after photobleaching, we report that viscosity in the lysosome increases significantly during cargo accumulation in several LSD models. In a mammalian cell culture model of Niemann Pick C, lysosomal viscosity directly correlates with the levels of accumulated cholesterol. We also observed increased viscosity in diverse LSD models in Caenorhabditis elegans, revealing that lysosomal viscosity is a powerful reporter with which to monitor substrate accumulation in LSDs for new diagnostics or to assay therapeutic efficacy.

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Section: Measurement Of Lysosomal Viscosity In Cell Culturementioning

confidence: 66%

Section: Measurement Of Lysosomal Viscosity In Cell Culturementioning

confidence: 99%

Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases

2018

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“…Proteins in coelomocytes, which are scavenger cells, play roles in efficient uptake of materials from the pseudocoelom and endosomal to lysosomal trafficking (Fares and Greenwald 2001). Following the uptake by coelomocytes, molecules travel through the endocytic compartments eventually going to lysosomes for degradation (Gee et al 2017). While the exact mechanism of MANF-1 role in coelomocytes is unknown, it is likely to affect lysosome function to maintain proteostasis.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inC. elegans

Taylor

Gupta

2023

Preprint

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The neurotrophic factor, Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), promotes neuronal health and survival. MANF is conserved in metazoans and necessary for the protection of dopaminergic neurons. The neuroprotective role of MANF involves regulation of the ER unfolded protein response (ER-UPR). Recent work has shown that MANF also functions in many other tissues and affects autophagy genes. Previously, we reported thatC. elegans manf-1mutants show defects including increased ER stress, α-Synuclein aggregation, and age-dependent dopaminergic neurodegeneration. In this study, we have further investigated manf-1’s function and describe its mechanism of action in regulating stress response, protein aggregation and aging. Our results showed that exposure to ER stress-inducing agents causedmanf-1transcription and protein expression to be upregulated. Consistent with the protective role ofmanf-1, mutant animals showed greater sensitivity to ER stress and died prematurely. We generatedmanf-1p::manf-1::mCherry(MANF-1OE) andhsp::manf-1transgenic strains overexpressing MANF and found that these animals had an extended lifespan, reduced protein aggregation, and increased neuronal health. Thein vivoanalysis of MANF-1 expression revealed that the protein was secreted and present in many tissues. Subcellular studies showed that MANF-1 was localized to lysosomes. We also observed that MANF-1OEworms had reduced LGG-1 and SQST-1/p62 levels, and increased expression and nuclear localization of the autophagy transcription factorhlh-30/TFEB. Thus, MANF-1 regulates protein homeostasis through increased lysosome activity and autophagic flux. Collectively, our work provides a novel understanding of MANF-1 function in promoting neuronal health, stress response, proteostasis, and lifespan of animals.

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“…Lysosomes are the terminal compartments in the endocytic pathway, where the pathogen internalized by endocytosis is eliminated [ 51 , 52 ]. In this study, we found that one hub DEmiR, i.e., miR-29-x, was significantly upregulated at 6 and 8 dpi.…”

Section: Discussionmentioning

confidence: 99%

Megalocytivirus Induces Complicated Fish Immune Response at Multiple RNA Levels Involving mRNA, miRNA, and circRNA

Ning

Sun

2021

IJMS

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Megalocytivirus is an important viral pathogen to many farmed fishes, including Japanese flounder (Paralichthys olivaceus). In this study, we examined megalocytivirus-induced RNA responses in the spleen of flounder by high-throughput sequencing and integrative analysis of various RNA-seq data. A total of 1327 microRNAs (miRNAs), including 368 novel miRNAs, were identified, among which, 171 (named DEmiRs) exhibited significantly differential expressions during viral infection in a time-dependent manner. For these DEmiRs, 805 differentially expressed target mRNAs (DETmRs) were predicted, whose expressions not only significantly changed after megalocytivirus infection but were also negatively correlated with their paired DEmiRs. Integrative analysis of immune-related DETmRs and their target DEmiRs identified 12 hub DEmiRs, which, together with their corresponding DETmRs, formed an interaction network containing 84 pairs of DEmiR and DETmR. In addition to DETmRs, 19 DEmiRs were also found to regulate six key immune genes (mRNAs) differentially expressed during megalocytivirus infection, and together they formed a network consisting of 21 interactive miRNA-messenger RNA (mRNA) pairs. Further analysis identified 9434 circular RNAs (circRNAs), 169 of which (named DEcircRs) showed time-specific and significantly altered expressions during megalocytivirus infection. Integrated analysis of the DETmR-DEmiR and DEcircR-DEmiR interactions led to the identification of a group of competing endogenous RNAs (ceRNAs) constituted by interacting triplets of circRNA, miRNA, and mRNA involved in antiviral immunity. Together these results indicate that complicated regulatory networks of different types of non-coding RNAs and coding RNAs are involved in megalocytivirus infection.

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Regulators of Lysosome Function and Dynamics inCaenorhabditis elegans

Cited by 7 publications

References 61 publications

Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases

Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases

Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inC. elegans

Megalocytivirus Induces Complicated Fish Immune Response at Multiple RNA Levels Involving mRNA, miRNA, and circRNA

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