Dihydroceramide Desaturase Promotes the Formation of Intraluminal Vesicles and Inhibits Autophagy to Increase Exosome Production

2021 ◽  
Author(s):  
Chen-Yi Wu ◽  
Jhih-Gang Jhang ◽  
Wan-Syuan Lin ◽  
Chih-Wei Lin ◽  
Li-An Chu ◽  
...  
Keyword(s):  
Dihydroceramide Desaturase

scholarly journals Dihydroceramide Desaturase Functions as an Inducer and Rectifier of Apoptosis: Effect of Retinol Derivatives, Antioxidants and Phenolic Compounds

2021 ◽  
Author(s):  
Mariam Alsanafi ◽  
Ryan D. R. Brown ◽  
Jeongah Oh ◽  
David R. Adams ◽  
Federico Torta ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
De Novo ◽  
Dynamic Balance ◽  
Proteasomal Degradation ◽  
Parp Cleavage ◽  
Chemical Stress ◽  
De Novo Synthesis ◽  
Concomitant Increase ◽  
Native Form ◽  
Dihydroceramide Desaturase

AbstractDihydroceramide desaturase (Degs1) catalyses the introduction of a 4,5-trans double bond into dihydroceramide to form ceramide. We show here that Degs1 is polyubiquitinated in response to retinol derivatives, phenolic compounds or anti-oxidants in HEK293T cells. The functional predominance of native versus polyubiquitinated forms of Degs1 appears to govern cytotoxicity. Therefore, 4-HPR or celecoxib appear to stimulate the de novo ceramide pathway (with the exception of C24:0 ceramide), using native Degs1, and thereby promote PARP cleavage and LC3B-I/II processing (autophagy/apoptosis). The ubiquitin-proteasomal degradation of Degs1 is positively linked to cell survival via XBP-1s and results in a concomitant increase in dihydroceramides and a decrease in C24:0 ceramide levels. However, in the case of 4-HPR or celecoxib, the native form of Degs1 functionally predominates, such that the apoptotic programme is sustained. In contrast, 4-HPA or AM404 do not produce apoptotic ceramide, using native Degs1, but do promote a rectifier function to induce ubiquitin-proteasomal degradation of Degs1 and are not cytotoxic. Therefore, Degs1 appears to function both as an ‘inducer’ and ‘rectifier’ of apoptosis in response to chemical cellular stress, the dynamic balance for which is dependent on the nature of chemical stress, thereby determining cytotoxicity. The de novo synthesis of ceramide or the ubiquitin-proteasomal degradation of Degs1 in response to anti-oxidants, retinol derivatives and phenolic compounds appear to involve sensors, and for rectifier function, this might be Degs1 itself.

Synthesis and Biological Activity of a Novel Inhibitor of Dihydroceramide Desaturase

ChemMedChem ◽  
2008 ◽  
Vol 3 (6) ◽  
pp. 946-953 ◽  
Author(s):  
Jose M. Munoz-Olaya ◽  
Xavier Matabosch ◽  
Carmen Bedia ◽  
Meritxell Egido-Gabás ◽  
Josefina Casas ◽  
...  
Keyword(s):  
Biological Activity ◽  
Dihydroceramide Desaturase

Dihydroceramide-desaturase-1-mediated caspase 9 activation through ceramide plays a pivotal role in palmitic acid-induced HepG2 cell apoptosis

APOPTOSIS ◽  
2016 ◽  
Vol 21 (9) ◽  
pp. 1033-1044 ◽  
Author(s):  
Qun Zhu ◽  
Jianjun Yang ◽  
Rongping Zhu ◽  
Xin Jiang ◽  
Wanlian Li ◽  
...  
Keyword(s):  
Palmitic Acid ◽  
Hepg2 Cell ◽  
Cell Apoptosis ◽  
Pivotal Role ◽  
Caspase 9 ◽  
Dihydroceramide Desaturase ◽  
Dihydroceramide Desaturase 1

Further characterization of rat dihydroceramide desaturase: Tissue distribution, subcellular localization, and substrate specificity

Lipids ◽  
2000 ◽  
Vol 35 (10) ◽  
pp. 1117-1125 ◽  
Author(s):  
Catherine Causeret ◽  
Luc Geeraert ◽  
Gerd Van der Hoeven ◽  
Guy P. Mannaerts ◽  
Paul P. Van Veldhoven
Keyword(s):  
Substrate Specificity ◽  
Subcellular Localization ◽  
Tissue Distribution ◽  
Dihydroceramide Desaturase

scholarly journals Ablation of Dihydroceramide Desaturase 1, a Therapeutic Target for the Treatment of Metabolic Diseases, Simultaneously Stimulates Anabolic and Catabolic Signaling

2013 ◽  
Vol 33 (11) ◽  
pp. 2353-2369 ◽  
Author(s):  
M. M. Siddique ◽  
Y. Li ◽  
L. Wang ◽  
J. Ching ◽  
M. Mal ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Metabolic Diseases ◽  
Dihydroceramide Desaturase ◽  
Dihydroceramide Desaturase 1

scholarly journals Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

2020 ◽  
Author(s):  
Rebecca Ward ◽  
Joanna J. Kaylor ◽  
Diego F. Cobice ◽  
Dionissia A. Pepe ◽  
Eoghan M. McGarrigle ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Bright Light ◽  
Immediate Early ◽  
Light Conditions ◽  
Photopic Vision ◽  
Wide Range ◽  
Dihydroceramide Desaturase ◽  
Cone Photopigments ◽  
Dihydroceramide Desaturase 1

AbstractCone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.

scholarly journals Dihydroceramide desaturase directs the switch between exosome production and autophagy for neuronal maintenance

2020 ◽  
Author(s):  
Chen-Yi Wu ◽  
Jhih-Gang Jhang ◽  
Chih-Wei Lin ◽  
Han-Chen Ho ◽  
Chih-Chiang Chan ◽  
...  
Keyword(s):  
Nervous System ◽  
Desaturase Gene ◽  
Dihydroceramide Desaturase ◽  
Autophagic Degradation ◽  
Photoreceptor Neurons ◽  
And Function ◽  
Neuronal Maintenance ◽  
Autophagy Inhibition

ABSTRACTExosomes play important roles in the nervous system. Mutations in the human dihydroceramide desaturase gene, DEGS1, are recently linked to severe neurological disorders, but the cause remains unknown. Here, we show that Ifc is required for the morphology and function of Drosophila photoreceptor neurons and not in the surrounding glia, but the degeneration of ifc-KO eyes can be rescued by glial expression of ifc, possibly mediated by exosomes. We develop an in vivo assay using Drosophila eye imaginal discs and show that the level and activity of Ifc correlates with the detection of exosome-like vesicles. While ifc overexpression and autophagy inhibition both enhances exosome production, combining the two had no additive effect. Moreover, ifc-KO reduces the density of the exosome precursor intraluminal vesicles (ILVs) in vivo, and DEGS1 promotes ILV formation in vitro. In conclusion, dihydroceramide desaturase promotes exosome formation and prevents its autophagic degradation in the nervous system.

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