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Targeted Sphingolipid analysis of HeLa silenced for or overexpressing GOLPH3 or LCS

ABSTRACT: A group of sequentially-acting enzymes operating at the branchpoint among sphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternae inter-conversion mechanisms. Through these effects, GOLPH3 controls the sub-Golgi localisation, and the lysosomal degradation rate of specific enzymes. Here we evaluated the impact of overexpressing or silencing GOLPH3 or its client enzyme lactosylceramide synthase (LCS) on the sphingolipid composition of HeLa cells by targeted lipid analysis.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Hela Cells

SUBMITTER: Giovanni D'Angelo

PROVIDER: ST001673 | MetabolomicsWorkbench | Fri Jan 29 00:00:00 GMT 2021

REPOSITORIES: MetabolomicsWorkbench

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Untargeted phospholipid analysis of HeLa silenced for or overexpressing GOLPH3

Project description:A group of sequentially-acting enzymes operating at the branchpoint among sphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternae inter-conversion mechanisms. Through these effects, GOLPH3 controls the sub-Golgi localisation, and the lysosomal degradation rate of specific enzymes. Here we evaluated the impact of overexpressing or silencing GOLPH3 on the glycerophospholipid composition of HeLa cells by untargeted lipid analysis.

2021-01-29 | ST001674 | MetabolomicsWorkbench

Targeted Sphingolipid analysis of human Fibroblasts silenced for or overexpressing GOLPH3 (part-I)

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Targeted Sphingolipid analysis of HeLa knockout for expression of GRASP55

Project description:Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 acts by binding to these enzymes and preventing their entry to COPI derived retrograde transport vesicles thus concentrating them in the trans-Golgi. In genome edited cells lacking GRASP55 the enzymes relocate to cis-Golgi. Here we evaluated the impact of deleting GRASP55 on sphingolipid composition of HeLa cells by targeted lipid analysis.

2021-07-18 | ST001877 | MetabolomicsWorkbench

Inhibiting sphingolipid synthesis improves outcomes and survival in GARP-mutant wobbler mouse, an ALS model

Project description:Defects of the endosomal and lysosomal systems have been increasingly linked to adult neurodegenerative diseases1,2. Deficiencies in the retrograde trafficking pathway between endosomes and the Golgi apparatus lead to forms of Alzheimer’s and Parkinson’s diseases in the case of retromer mutations, or to the rare progressive cerebello-cerebral atrophy type 2 (PCCA2) for mutations of the Golgi-associated retrograde protein (GARP) complex3. Mutations in GARP subunits lead to abnormal cellular lipid metabolism, with accumulation of sterol esters and sphingoid bases, and concomitant lysosomal dysfunction in yeast, murine, or human cells4,5. However, whether these lipid changes cause neurodegeneration and if so, which lipids are toxic, is unknown. Here, we show that GARP defects lead to global changes of cellular protein distribution, including missorting of numerous disease-linked enzymes of sphingolipid metabolism, and to the accumulation of sphingolipid intermediates in wobbler fibroblasts. Inhibiting sphingolipid synthesis in wobbler mice, a murine model of GARP deficiency with features of amyotrophic lateral sclerosis (ALS), improved wellness scores and grip strength, and increased lifespan. Our findings indicate that regulation of sphingolipids by the GARP complex is essential for neuronal health and suggest that inhibition of sphingolipid synthesis might provide a therapeutic strategy for treatment of neurodegenerative diseases due to defects in retrograde endosome-to-Golgi membrane trafficking.

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Identification of human genes of which expression are induced by 4MU-xyloside treatment

Project description:The Golgi stress response is a homeostatic mechanism that augments the functional capacity of the Golgi apparatus when Golgi function becomes insufficient (Golgi stress). Three response pathways of the Golgi stress response have been identified in mammalian cells, the TFE3, HSP47 and CREB3 pathways, which augment the capacity of specific Golgi functions such as N-glycosylation, anti-apoptotic activity and pro-apoptotic activity, respectively. On the contrary, glycosylation of proteoglycans (PGs) is another important function of the Golgi, although the response pathway upregulating expression of glycosylation enzymes for PGs in response to Golgi stress remains unknown. Here, we found that expression of glycosylation enzymes for PGs was induced upon insufficiency of PG glycosylation capacity in the Golgi (PG-Golgi stress), and that transcriptional induction of genes encoding glycosylation enzymes for PGs was independent of the known Golgi stress response pathways and ER stress response. Promoter analyses of genes encoding these glycosylation enzymes revealed the novel enhancer element PGSE, which regulates their transcriptional induction upon PG-Golgi stress. From these observations, the response pathway we discovered is a novel Golgi stress response pathway, which we have named the PG pathway.

2018-08-01 | GSE117938 | GEO

Identification of human gene expression induced by 4MU-xyloside treatment

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Project description:Sequentially acting Sox transcription factors in neural lineage development

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N-terminome analyses of the intramembrane-cleaving protease SPPL3

Project description:The intramembrane protease SPPL3 can specifically cleave select Golgi enzymes, enabling their secretion and concomitantly altering global cellular glycosylation, yet the entire range of Golgi glycan-modifying enzymes cleaved by SPPL3 under physiological conditions remains to be defined. Here, we established isogenic SPPL3-deficient HEK293 and HeLa cell lines and applied N-terminomics to identify substrates cleaved by endogenous SPPL3 and released into conditioned cell culture supernatants.

2022-03-17 | PXD028769 | Pride

Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans [RNA-Seq]

Project description:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

2023-09-08 | GSE240425 | GEO

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