OCaR1, a gatekeeper of lysosomal and granular Ca2+ release and regulated exocytosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA434189 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6728210.fastq.gz | Fastqsanger.gz | |||
| SRR6728211.fastq.gz | Fastqsanger.gz | |||
| SRR6728212.fastq.gz | Fastqsanger.gz | |||
| SRR6728213.fastq.gz | Fastqsanger.gz | |||
| SRR6728208.fastq.gz | Fastqsanger.gz |
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Project description:During exocytosis, a Ca2+ increase arises in close vicinity of secretory granules which is strictly prevented in resting cells. Granular Ca2+ homeostasis and its role in granular exocytosis are not well understood.
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2023-05-15 | GSE185911 | GEO
Project description:Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we assured that paucimannosidic proteins in cancer cells are produced by lysosomal glycoside hydrolases and secreted via regulated lysosomal exocytosis, a process in which lysosomes are directly fused with the plasma membrane. Interestingly, lysosomal exocytosis preferentially occurred in the vicinity of focal adhesions, protein complexes connecting the actin cytoskeleton to the extracellular matrix. Through genome-wide knockout screening, we identified that MYO18B, an actin crosslinker, is required for focal adhesion maturation, facilitating lysosomal exocytosis and release of lysosomal proteins to the extracellular milieu. Our data suggest that the mechanosensitive cation channel PIEZO1 locally activated at focal adhesions imports Ca2+ necessary for lysosome-plasma membrane fusion. Collectively, our study unveiled an intimate relationship between lysosomal exocytosis and focal adhesion, shedding light on the unexpected interplay between lysosomal activities and cellular mechanosensing in cancer.
2025-01-14 | PXD051592 | Pride
Project description:Epigenetic changes drive differential gene expression, contributing to oncogenic transformation and drug resistance. Lysosomes are crucial in cell signaling and the sequestration of toxins and chemotherapeutic agents. This sequestration followed by expulsion through lysosomal exocytosis is a factor in drug resistance. The epigenetic regulation of lysosomal exocytosis remains poorly understood. Our research focuses on this regulation, hypothesizing that epigenetic modifier drugs (epidrugs) capable of inhibiting lysosomal exocytosis and could serve as potential therapeutics. Additionally, we investigate their potential synergy with drugs known to be sequestered in lysosomes. To examine this concept, we screened approximately 150 epigenetic drugs targeting various reader, writer, or eraser proteins. These drugs were assessed for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and on lysosomal biogenesis. Our findings reveal that among the epidrugs showing synergy with cisplatin and further reducing cell viability in combination, two type I PRMT inhibitors, MS023 and GSK3368715, inhibited lysosomal exocytosis. Notably, neither of these drugs altered the expression of the CLEAR lysosomal biogenesis network of genes, suggesting the involvement of novel regulators in lysosomal functions. To explore the specific components of the trafficking machinery affected by PRMT inhibitors, we conducted an RNA-seq analysis, uncovering several differentially expressed genes (DEGs). In addition to previously described functions such as methylation activity, or DNA repair; these DEGs included those involved in vesicular trafficking, lysosomal enzyme activity and lysosome dynamics, offering potential insights into the mechanism of reduced exocytosis and identifying a novel mode for its regulation. Additionally, both inhibitors exhibited synergy with other drugs known to be sequestered in lysosomes, such as carboplatin, oxaliplatin, sunitinib, and doxorubicin, indicating that inhibition of lysosomal exocytosis may be a common phenomenon for such drugs. These findings underscore the potential of Type I PRMT inhibitors as therapeutic agents in cancer treatment. Consistently, analysis on the publicly available patient data revealed that lower levels of type I PRMTs (PRMT1 and 6) were associated with better patient response to these drugs, further suggesting their potential as drug candidates for combination therapy to enhance chemotherapy efficacy and improve cancer patient survival rates.
2025-08-13 | GSE277490 | GEO
Project description:The clearance of dead adipocytes in adipose tissue (AT) poses a major challenge due to their large size, which exceeds the phagocytic capacity of macrophages and prevents classical, anti-inflammatory efferocytosis. Instead, adipose tissue macrophages (ATMs) accumulate around dying adipocytes, forming crown-like structures (CLS), and engage in lysosomal exocytosis – the extracellular degradation of adipocytes. In this study, we used an ex vivo explant model of murine epididymal white AT, cultured over seven days to investigate pharmacological strategies that modulate lysosomal exocytosis. We observed a progressive increase in CLS formation, secretion of the lysosomal enzymes ß-Hexosaminidase A (HEXA) and lysosomal acid lipase (LAL), and surface abundance of LAMP1 and LAMP2, confirming ATMs as key mediators of this process. Notably, activation of lysosomal exocytosis with the mTOR inhibitor Rapamycin enhanced adipocyte clearance and significantly reduced inflammatory ATM abundance and TNF-α secretion. Bulk RNA sequencing of ATMs revealed a highly significant impact of Rapamyin on ATM proliferation. In contrast, inhibition of lysosomal exocytosis with PIKfyve inhibitor Apilimod or targeted inhibition of LAL using Lalistat-2 disrupted lysosomal function and promoted a pro-inflammatory ATM phenotype. Our findings highlight lysosomal exocytosis as a critical pathway for the resolution of dead adipocytes and the regulation of inflammation in adipose tissue. Pharmacological enhancement of this process may represent a promising therapeutic approach to attenuate inflammation in AT and its metabolic consequences, including insulin resistance and type 2 diabetes.
2025-09-03 | GSE307090 | GEO
Project description:Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis
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Project description:Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca2+ channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood. Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. Beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using mRNA-sequencing and quantitative PCR. Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells. Tspan7-knockout mice (Tspan7 y/- mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan7y/- islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan7y/- beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in high K+-stimulated insulin secretion. Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta cell line (EndoC-H1) following Tspan7 KD. Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts
2022-10-10 | GSE213730 | GEO
Project description:Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca2+ channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood. Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. Beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using mRNA-sequencing and quantitative PCR. Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells. Tspan7-knockout mice (Tspan7 y/- mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan7y/- islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan7y/- beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in high K+-stimulated insulin secretion. Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta cell line (EndoC-bH1) following Tspan7 KD. Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts
2022-10-10 | GSE213729 | GEO
Project description:Epidrug Screening Identifies Type I PRMT Inhibitors as Modulators of Lysosomal Exocytosis and Drug Sensitivity in Cancers
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