Sphingomyelin and RNase-resistant RNA in Microdomains of the Inner Nuclear Membrane
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ABSTRACT:
PROVIDER: PRJNA1091890 | ENA |
REPOSITORIES: ENA
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Project description:Nuclear lipid microdomains rich in sphingomyelin and cholesterol content regulate double-stranded exonuclease-resistant RNA. The study aimed to elucidate the importance of nuclear lipid microdomains in safeguarding nuclear RNA from digestion and to scrutinize all RNA present. Thus, we investigated the impact of sphingomyelinase on nuclear lipid microdomain RNA and conducted RNA extraction, library preparation, and sequencing. Sphingomyelinase treatment makes the RNA susceptible to RNase treatment. Nuclear lipid microdomains exhibit a higher abundance of retained introns, small nuclear RNA, and long intergenic non-coding RNA compared to whole nuclei, with a notable enrichment in miRNA. The high concentration (20%) of miRNAs in nuclear lipid microdomains is justified by the presence of specific nuclear circular RNA as exons circularized with 'retained' introns, referred to as exon-intron circular RNA (EIciRNA) that act as a sponge for miRNAs. Moreover, we demonstrate the presence of ciRNA. The functional analysis indicates that all types of RNase-resistant RNA associated with nuclear lipid microdomains are involved in chromatin organization and brain pathophysiology. In conclusion, nuclear lipid microdomains represent a site of transcription regulation in which circular RNAs, miRNA, and double-stranded mRNA, all resistant to RNase, are stabilized by nuclear sphingomyelin.
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Project description:Cholesterol-rich microdomains are membrane dynamic compartments characterized by specific lipid and protein composition and present in all cell types. These assemblies are involved in several biological processes, including infection by intracellular pathogens. This work provides a comprehensive analysis of the composition and organization of human erythrocyte membrane microdomains
2020-11-05 | MSV000086413 | MassIVE
Project description:Analysis of Pseudomonas aeruginosa PAO1 treated with 200 µM sphingomyelin. Results provide insight into the response to sphingomyelin in P. aeruginosa.
2017-02-12 | GSE83078 | GEO
Project description:Lysosomal storage diseases are congenital lipid metabolism disorders, often accompaning by male infertility. Sms1, the enzyme, that generates sphingomyelin from ceramides seems to be involved in spermatogeneis and spermiogenesis. Therefore, testis but also muscle and brain of a mouse line carrying an insertional mutation in Sms1 were analysed. Total RNA obtained from 4 male mutant mice was compared to four wild type controls.
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271335 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
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Project description:Lysosomal storage diseases are congenital lipid metabolism disorders, often accompaning by male infertility. Sms1, the enzyme, that generates sphingomyelin from ceramides seems to be involved in spermatogeneis and spermiogenesis. Therefore, testis but also muscle and brain of a mouse line carrying an insertional mutation in Sms1 were analysed.
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Project description:Sphingomyelin synthase (SMS) 2 is the synthetic enzyme of sphingomyelin (SM), which regulates the fluidity and microdomain structure of the plasma membrane. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis, and found suppression of DSS-induced inflammation in SMS2 deficient (SMS2-/-) mice. Results provide insight into the role of SMS2 in inflammation.
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