Sphingolipid metabolism in senescence (Homo sapiens)

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812813333141413443423, 134131343931369142818431211112399132313387393989131231243443337139Telomere maintainanceProliferationSenescence escapeDNA damageCytokine releasede novo biosynthesis3Protein kinase C beta typeGlucosylceramidaseS1PR1GlucosylceramidePLCSGPP1SenescenceC18-dihydrosphingosineceramidesCDK2E2F1SGMS2P38lactosylceramideDEGS1SenescenceSPHK1PP2SASPOncogene induced senescenceGLB1SenescenceProtein kinase C alpha typeS1PR2p21Sphingosine-1-phosphatePhosphatidylcholinesPalmitoyl-CoACeramide glucosyltransferaseSphingosine RB1Telomerase reverse transcriptaseS1PR5PP13-ketodihydrosphingosineCERS4Serine palmitoyltransferase 1RB1CDK4DihydroceramidesMTORCERS2MAPK1diacylglycerols3-ketodihydrosphingosine reductasesphingomyelinsNeutral sphingomyelinase 2ASAH1serinep53 ProliferationPsalvage pathwayhydrolysis of complex sphingolipids3NF-κB3


Sphingolipids, which include sphingomyelins, sphingosines and ceramides are bioactive bioactive molecules present in all eukaryotic cells, are important in regulating various aspects of cell biology, such as cell cycle, proliferation, and even senescence (Trayssac et al., 2018). Evidence shows that ceramide metabolism is deregulated in cellular senescence and can even induce it. (Venable et al., 2006).

Ceramides are thought to induce senescence in a p53 dependent and independent manner by hypophosphorylated retinoblastoma protein (Lee et al., 2000; Dix 2018; Jeffries & Krupenko, 2018). Ceramides function both down- and upstream of p53 (Jeffries et al., 2018). p53 mediates the interference of the phosphorylation of retinoblastoma-like protein RBL1 and RBL through the cyclin-dependent kinase inhibitor p21 (Jeffries et & Krupenko, 2018). Additionally, p53 has been demonstrated to directly activate ceramide synthase. (Jeffries & Krupenko, 2018). Consequently, this implies a feedback mechanism between ceramides and the tumor suppressor. Ceramide also interacts directly with human telomerase reverse transcriptase (hTERT) by inhibiting it, therefore causing telomere instability (Hannun & Obeid, 2002; Deevska et al., 2021).

Ceramides activate protein phosphatase 1 and 2A (PP1 and PP2A), which increases the levels of p21 (Trayssac et al., 2018). This then inhibits the cyclin dependent kinase 2 (CDK2) and CDK4. As a consequence, the retinoblastoma protein is hypophosphorylated and induces senescence (Lee et al., 2000; Dix 2018). The hypophosphorylated retinoblastoma protein leads to the inhibition of E2F (Dix, 2018; Jeffries & Krupenko, 2018). This group of genes is normally responsible for cell proliferation and therefore their inhibition causes senescence (Dix 2018). In addition to that, PP1 and PP2A directly interfere with Rb by dephosphorylating it (Dix 2018). These two phosphatases also inhibit the mTOR pathway that is associated with cell proliferation (Millner & Atilla-Gokcumen, 2020).

Sphingosine-1-phosphate (S1P) is thought to induce cell proliferation and migration by binding to S1PR1 and S1PR5. This is downregulated in senescence (Trayssac et al., 2018). In cellular senescence, S1P has been shown to be depleted as a result of a downregulation of sphingosine kinase 1 (SPHK1), induced by p53. The downregulation of SK1 is thought to be due to its degradation induced by p53 (Kim et al., 2019). Moreover, S1P has hTERT as a direct target and promotes its stability (Magali et al., 2021). Furthermore, there is an increase in S1P binding to the S1P receptor 2 (S1PR2), which has been associated with the release of pro-inflammatory cytokines and therefore the SASP. S1P is also thought to inhibit ceramide synthase 2 (CERS2), which catalyzes the conversion of sphingosine into ceramide (Magali et al., 2021).

Sphingosine is increased in senescence cells by the increase of S1P-phopshatase (SGPP1) and the increase in acid ceramidase ASAH-1 SGPP1 catalyzes the conversion of S1P to sphingosine, while ASAH-1 catalyzes the conversion of ceramide to sphingosine (Munk et al., 2021; Kim et al., 2019). This causes the dephosphorylation of retinoblastoma protein, which further causes senescence (Trayssac et al., 2018).

Ceramide can be synthesized de novo starting with the conversion of palmitoyl-CoA and serine to 3-ketodihydrosphingosine. Upregulation of ceramide synthase 4 (CERS4), which converts dihydro-sphingosine into dihydro-ceramide. CERS4 has been thought to be a key enzyme in two types of senescence: OIS and replicative senescence, by mediating its effects through the PP1-Rb-E2F axis (Dix, 2018)

Galactosidase β1 (GLB1) and in glucosylceramidase (GBA), which catalyze the conversion of lactosylceramide to glucosylceramide and the conversion of glucosylceramide to ceramide, respectively, are upregulated in cellular senescence. Additionally, there is a decrease in glucosylceramidase synthase, which catalyzes the formation of glucosylceramide from ceramide (Flor et al., 2017).

Activation of p53, due to DNA damage, leads to an increase of neutral sphingomyelinase 2 (nSMase 2) (Deevska et al., 2021; Jeffries & Krupenko, 2018). Moreover, it has been noted that in senescent cells, there are elevated levels of neutral sphingomyelinases ( Millner & Atilla-Gokcumen, 2020). These enzymes catalyze the conversion of sphingomyelin to ceramide (Gey & Seeger, 2013).

Elevated ceramide levels result in elevated diacylglycerol (DAG) levels (Deevska et al., 2021). These two lipids are linked by sphingomyelin synthase 2 (SGMS2). SGMS2 catalyzes the transfer of a phosphorycholine group from phosphatidylcholine to ceramide, yielding sphingomyelin and DAG. In cellular senescence, SMS was found to be overexpressed. This caused an increase in DAG which caused the chronic activation of its downstream effectors. This causes the downregulation of protein kinase C α and β (PKCα and β) via the prolonged activation of phospholipase C. The consequences of this is the activation of p53 and p38, leading to SASP and senescence (Deevska et al., 2021).

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  1. Trayssac M, Clarke CJ, Stith JL, Snider JM, Newen N, Gault CR, Hannun YA, Obeid LM; ''Targeting sphingosine kinase 1 (SK1) enhances oncogene-induced senescence through ceramide synthase 2 (CerS2)-mediated generation of very-long-chain ceramides.''; Cell Death Dis, 2021 PubMed Europe PMC Scholia
  2. Gault CR, Obeid LM, Hannun YA; ''An overview of sphingolipid metabolism: from synthesis to breakdown.''; Adv Exp Med Biol, 2010 PubMed Europe PMC Scholia
  3. Trayssac M, Hannun YA, Obeid LM; ''Role of sphingolipids in senescence: implication in aging and age-related diseases.''; J Clin Invest, 2018 PubMed Europe PMC Scholia
  4. Deevska G, Dotson PP 2nd, Mitov M, Butterfield DA, Nikolova-Karakashian M; ''Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane.''; Cells, 2021 PubMed Europe PMC Scholia
  5. ''Ceramide synthase 4: a novel metabolic regulator of oncogene-induced senescence''; ,
  6. Hannun YA, Obeid LM; ''The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind.''; J Biol Chem, 2002 PubMed Europe PMC Scholia
  7. Munk R, Anerillas C, Rossi M, Tsitsipatis D, Martindale JL, Herman AB, Yang JH, Roberts JA, Varma VR, Pandey PR, Thambisetty M, Gorospe M, Abdelmohsen K; ''Acid ceramidase promotes senescent cell survival.''; Aging (Albany NY), 2021 PubMed Europe PMC Scholia
  8. Millner A, Atilla-Gokcumen GE; ''Lipid Players of Cellular Senescence.''; Metabolites, 2020 PubMed Europe PMC Scholia
  9. Flor AC, Wolfgeher D, Wu D, Kron SJ; ''A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.''; Cell Death Discov, 2017 PubMed Europe PMC Scholia
  10. Weinstein IB; ''Cell culture studies on the mechanism of action of chemical carcinogens and tumor promoters.''; Carcinog Compr Surv, 1985 PubMed Europe PMC Scholia
  11. Kim MK, Lee W, Yoon GH, Chang EJ, Choi SC, Kim SW; ''Links between accelerated replicative cellular senescence and down-regulation of SPHK1 transcription.''; BMB Rep, 2019 PubMed Europe PMC Scholia
  12. Jeffries KA, Krupenko NI; ''Ceramide Signaling and p53 Pathways.''; Adv Cancer Res, 2018 PubMed Europe PMC Scholia
  13. Dix FL; ''Ceramide synthase 4: a novel metabolic regulator of oncogene-induced senescence''; University Edinburgh, 2018
  14. Gey C, Seeger K; ''Metabolic Changes Investigated by Proton NMR Spectroscopy in Cells Undergoing Oncogene-Induced Senescence.''; Methods Mol Biol, 2017 PubMed Europe PMC Scholia


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119472view08:00, 30 June 2021TadeIdowuDeletion additional p53
119413view11:16, 28 June 2021DKalbeGrouping
119409view14:21, 27 June 2021TadeIdowuNF-κB
119383view12:50, 25 June 2021DKalbeLayout
119382view12:48, 25 June 2021DKalbecolor coding
119381view12:00, 25 June 2021TadeIdowuArrangment
119377view11:48, 25 June 2021TadeIdowuAnnotation
119375view10:48, 25 June 2021EweitzOntology Term : 'aging pathway' added !
119371view10:40, 25 June 2021EweitzOntology Term : 'sphingolipid metabolic pathway' added !
119370view10:34, 25 June 2021EweitzModified title
119338view08:59, 24 June 2021DKalbeData nodes
119336view08:30, 24 June 2021DKalbeDescription
119335view08:26, 24 June 2021DKalbeDescription
119334view08:19, 24 June 2021DKalbeReferencing
119325view15:14, 23 June 2021DKalbeCorrecting references
119324view15:05, 23 June 2021DKalbeCorrecting errors
119323view14:50, 23 June 2021JDoreenModified description
119219view16:18, 22 June 2021TadeIdowuModified description
119218view15:09, 22 June 2021DKalbeadjusting references in description
119217view15:06, 22 June 2021TadeIdowuModified description
119216view14:49, 22 June 2021DKalbeDescription layout
119215view14:46, 22 June 2021DKalbeDescription of the pathway
119211view14:14, 22 June 2021Mario5181Modified title
119208view14:08, 22 June 2021DKalbeRearranging, adding references and correcting
119207view12:21, 22 June 2021TadeIdowuModified title
119206view12:20, 22 June 2021TadeIdowuNew pathway

External references


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NameTypeDatabase referenceComment
3-ketodihydrosphingosine reductaseProteinQ06136 (Uniprot-TrEMBL)
3-ketodihydrosphingosineMetaboliteCHEBI:17862 (ChEBI)
ASAH1GeneProductENSG00000104763 (Ensembl)
C18-dihydrosphingosineMetaboliteCHEBI:16566 (ChEBI)
CDK2GeneProductENSG00000123374 (Ensembl)
CDK4GeneProductENSG00000135446 (Ensembl)
CERS2GeneProductENSG00000143418 (Ensembl)
CERS4GeneProductENSG00000090661 (Ensembl)
Ceramide glucosyltransferaseProteinQ16739 (Uniprot-TrEMBL)
DEGS1GeneProductENSG00000143753 (Ensembl)
DihydroceramidesMetaboliteCHEBI:139048 (ChEBI)
E2F1GeneProductENSG00000101412 (Ensembl)
GLB1GeneProductENSG00000170266 (Ensembl)
GlucosylceramidaseProteinA0A068F658 (Uniprot-TrEMBL)
GlucosylceramideMetaboliteCHEBI:18368 (ChEBI)
MAPK1GeneProduct5594 (Entrez Gene)
MTORGeneProductENSG00000198793 (Ensembl)
NF-κBPathwayWP4562 (WikiPathways)
Neutral sphingomyelinase 2GeneProductENSG00000103056 (Ensembl)
Oncogene induced senescencePathwayWP3308 (WikiPathways)
P38GeneProductENSG00000152464 (Ensembl)
PLCProteinA0A087WT80 (Uniprot-TrEMBL)
PP1ProteinQ27088427 (Wikidata)
PP2ProteinQ7120082 (Wikidata)
Palmitoyl-CoAMetaboliteCHEBI:15525 (ChEBI)
PhosphatidylcholinesMetaboliteCHEBI:49183 (ChEBI)
Protein kinase C alpha typeProteinP17252 (Uniprot-TrEMBL)
Protein kinase C beta typeProteinP05771 (Uniprot-TrEMBL)
RB1GeneProductENSG00000139687 (Ensembl)
S1PR1GeneProductENSG00000170989 (Ensembl)
S1PR2GeneProductENSG00000267534 (Ensembl)
S1PR5GeneProductENSG00000180739 (Ensembl)
SASPPathwayWP3391 (WikiPathways)
SGMS2GeneProductENSG00000164023 (Ensembl)
SGPP1GeneProductENSG00000126821 (Ensembl)
SPHK1GeneProductENSG00000176170 (Ensembl)
SenescencePathwayWP615 (WikiPathways)
Serine palmitoyltransferase 1ProteinO15269 (Uniprot-TrEMBL)
Sphingosine MetaboliteCHEBI:45719 (ChEBI)
Sphingosine-1-phosphateMetaboliteCHEBI:37550 (ChEBI)
Telomerase reverse transcriptaseProteinO14746 (Uniprot-TrEMBL)
ceramidesMetaboliteCHEBI:17761 (ChEBI)
diacylglycerolsMetaboliteCHEBI:18035 (ChEBI)
lactosylceramideMetaboliteCHEBI:134507 (ChEBI)
p21ProteinA0A024RCX5 (Uniprot-TrEMBL)
p53 MetaboliteCHEBI:77731 (ChEBI)
serineMetaboliteCHEBI:17822 (ChEBI)
sphingomyelinsMetaboliteCHEBI:62490 (ChEBI)

Annotated Interactions

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