Regulation of the lysosome by sphingolipids: Potential role in aging

Tang, Haiqing; Huang, Xiaokun; Pang, Shijin

doi:10.1016/j.jbc.2022.102118

Cited by 13 publications

(8 citation statements)

References 115 publications

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“…This suggested that sphingomyelin might be crucial for invasive protrusion formation. Sphingomyelin composes ∼ 5% of membrane lipids and is found in the plasma membrane and endolysosome, where it plays roles in signaling, vesicle and protein trafficking, membrane stability, and lysosome function (Duran et al, 2012; Goni, 2022; Tang et al, 2022). We knocked down sms-1 in the AC-specific RNAi strain and found that loss of sms-1 diminished the formation and growth of the invasive protrusion (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Loss of the sphingomyelin synthase SMS-1 also reduced AC lysosomes prior to invasion. Although sphingomyelin composes only ∼5% of lipids in most cells, it is made in the Golgi and concentrated in the plasma membrane and within the endolysosome and is important for membrane stability (Goni, 2022; Tang et al, 2022), and thus its loss could affect lysosome stores. Sphingomyelin is also crucial for vesicle biogenesis at the Golgi (Duran et al, 2012), and sphingomyelin reduction possibly reduces the trafficking of phospholipids from the trans-Golgi to the lysosome (Liu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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De novo lipid synthesis and polarized prenylation drives cell invasion through basement membrane

Park,

Garde,

Thendral

et al. 2024

Preprint

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SummaryInvasive cells form large, specialized protrusions to break through basement membrane (BM) matrix barriers. Park et al., reveal a crucial requirement for de novo lipid synthesis and a dynamic polarizing prenylation system to rapidly construct invasive protrusions that breach BMs.To breach basement membrane (BM), cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi duringC. elegansanchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC’s invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that the endoplasmic reticulum (ER)-associated HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, enriches at the AC invasive front, and that the final ER prenylation enzyme, ICMT-1, localizes to ER exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

De novo lipid synthesis and polarized prenylation drives cell invasion through basement membrane

Park,

Garde,

Thendral

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…To control the environment inside the organelle, the lysosome is tightly packed with sphingolipids (Tang et al, 2022). However, the lysosomal membrane can be damaged under stressful conditions.…”

Section: Lysosomal Injury and Repairing Mechanismsmentioning

confidence: 99%

Lysosomal dysfunction in diabetic cardiomyopathy

Kobayashi

Hahn²,

Silverstein³

et al. 2023

Front. Aging

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Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

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“…4). Various sphingolipids have been shown to contribute to organismic aging and age-associated pathologies [30][31][32] . We identify LPD-3 as a critical megaprotein regulator of the phospholipid-sphingolipid rheostat, dysfunction of which can profoundly affect aging via insulin/mTOR.…”

mentioning

confidence: 99%

LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling inC. elegans

Pandey

Wang

et al. 2023

Preprint

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Decreased insulin-mTOR signaling enables exceptional longevity in the nematode C. elegans by activating geroprotective transcription factors, including DAF-16, SKN-1 and HSF-1. Few studies have examined whether and how increased insulin-mTOR may actively drive organismic aging. Here we show that an agonist insulin INS-7 is drastically over-produced and causes shortened lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Kučinskas syndrome. Lipidomic profiling reveals marked increase in the abundance of hexaceramide species in lpd-3 mutants, consistent with up-regulation of the genes encoding biosynthetic enzymes for hexaceramides, including HYL-1 (Homolog of Yeast Longevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the shortened lifespan of lpd-3 mutants through InsR/DAF-2 and mTOR/LET-363. We propose that increased insulin signaling exhibits late-life antagonistic pleiotropy and shortens lifespans through sphingolipid-hexaceramide and mTOR regulatory pathways.

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Regulation of the lysosome by sphingolipids: Potential role in aging

Cited by 13 publications

References 115 publications

De novo lipid synthesis and polarized prenylation drives cell invasion through basement membrane

De novo lipid synthesis and polarized prenylation drives cell invasion through basement membrane

Lysosomal dysfunction in diabetic cardiomyopathy

LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling inC. elegans

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