A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest
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ABSTRACT:
PROVIDER: PRJNA418450 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6293390_1.fastq.gz | Fastqsanger.gz | |||
| SRR6293390_2.fastq.gz | Fastqsanger.gz | |||
| SRR6293400_1.fastq.gz | Fastqsanger.gz | |||
| SRR6293400_2.fastq.gz | Fastqsanger.gz | |||
| SRR6293391_1.fastq.gz | Fastqsanger.gz |
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Project description:Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose-loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids ( i.e., sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp-1 on the PM of sucrose-loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose-loaded fibroblasts. The inhibition of ?-glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment.-Samarani, M., Loberto, N., Soldà, G., Straniero, L., Asselta, R., Duga, S., Lunghi, G., Zucca, F. A., Mauri, L., Ciampa, M. G., Schiumarini, D., Bassi, R., Giussani, P., Chiricozzi, E., Prinetti, A., Aureli, M., Sonnino, S. A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest.
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Project description:HDL particles are known to possess several anti-atherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant and antiinflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Methods Eight weeks old EKO mice, EKO mice overexpressing human apoA-I (EKO/hA-I) and wild-type mice as controls were fed either Chow or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyse the transcriptome of the aorta of the three genotypes in each experimental condition. Results: In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of the immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway Conclusions. ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response
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Project description:Despite accumulating evidences linking defective lysosome function with autoimmune diseases, how the catabolic machinery is regulated for immune homeostasis remains largely unknown. Lamtor5 is a subunit of the Ragulator mediating mTORC1 activation in response to amino acids, but its action mode and physiological role are yet to be addressed. Here we unexpectedly found that myeloid Lamtor5 ablating mice developed spontaneous inflammation and systemic lupus erythematosus (SLE)-like manifestation. Loss of Lamtor5 in macrophages caused impaired vacuolar H⁺-ATPase (v-ATPase) activity, lysosome de-acidification, and aberrant mTORC1 activation, correlating with undesirable inflammatory responses. Mechanistically, we showed that Lamtor5 physically associated with ATP6V1A, an essential subunit of v-ATPase, and promoted the V0/V1 holoenzyme assembly for lysosome acidification. Notably, binding of Lamtor5 to v-ATPase substantially affected lysosomal tethering of Rag GTPase and weakened its interaction with mTORC1 for activation. Importantly, defective Lamtor5 expression, along with impaired lysosomal function and hyperactivation of mTORC1, was corroborated in peripheral blood mononuclear cells (PBMCs) of SLE patients and correlated with disease severity. Overall, our findings establish Lamtor5 as a new lysosome regulator, and elucidate an unappreciated mechanism that coordinates catabolic and anabolic pathways to bolster immune homeostasis preventing autoimmunity.
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Project description:Herein, we develop a novel lysosome-localizable reactive diazirine molecule MDA and demonstrate its enhanced labeling capability in lysosomal microenvironment. Further, we develop a novel microenvironment-specific enrichment (MiSE) strategy for profiling lysosomal proteome, containing MDA-based labeling and affinity enrichment. We demonstrate the effectiveness of MiSE in profiling the lysosomal proteome of living SH-SY5Y cells, identifying 1651 lysosomal proteome, including 126 lysosome-annotated proteins. Furthermore, we utilize MiSE coupled with data-independent acquisition (DIA) analysis to investigate the dynamic changes in the lysosomal proteome in SH-SY5Y cells upon ubiquitin-proteasome system (UPS) inhibition using four proteasome inhibitors. Our results reveal 117 UPS-inhibition related lysosomal proteins, highlighting their involvement in stress response and cell cycle regulation. Notably, we observe distinct proteomic signatures for each inhibitor, suggesting the unique mechanisms of lysosomal response to UPS inhibition.
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