Sphingolipids and the unfolded protein response

Bennett, Melissa K.; Wallington-Beddoe, Craig T.; Pitson, Stuart M.

doi:10.1016/j.bbalip.2019.06.002

Cited by 23 publications

(22 citation statements)

References 103 publications

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“…These results indicate that SPHK2 is the main target responsible for the toxicity of SPHK inhibitors and further raise doubts on whether the S1P/ceramide balance is the main determinant of their toxicity. An alternative model is that this toxicity derives from perturbations in membrane fluidity generated after SPHK2 inhibition through the accumulation of ceramide, which would then activate the UPR and ISR (25,38). Moreover, while SPHK1 is predominantly cytoplasmic, SPHK2 is mainly associated to the ER and mitochondrial membranes (39), supporting a direct effect of SPHK2 inhibitors in the ER composition.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon was accompanied by a deattachment of ribosomes from ER membranes, potentially contributing to the overall reduction in protein synthesis triggered by SKI-II. Nevertheless, changes in ER morphology can be produced directly by changes in the cellular lipid composition or as a consequence of an activation of PERK-dependent signaling of the Unfolded Protein Response (UPR) (25,26). To distinguish between these two possibilities, we compared the effects of SKI-II to those of Thapsigargin, a compound that inactivates Ca 2+ -dependent chaperones necessary for protein folding in the ER and thus activates the UPR (27).…”

Section: C) Supporting This View Transition Electron Microscopy (Tmentioning

confidence: 99%

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A chemical screen identifies a link between lipid metabolism and mRNA translation

Fernández-Capetillo¹,

Corman

Kanellis

et al. 2020

Preprint

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mRNA translation is one of the most energy-demanding processes for living cells, alterations of which have been frequently documented in human disease. Using recently developed technologies that enable image-based quantitation of overall translation levels, we here conducted a chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. Consistent with current knowledge, inhibitors of the mTOR signaling pathway were the most represented class among translation suppresors. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum, which activates the integrated stress response (ISR). Accordingly, the impact of SPHK inhibitors on translation is alleviated by the concomitant inhibition of ISR kinases. On the other hand, and despite the large number of molecules tested, our study failed to identify chemicals capable of substantially increasing mRNA translation, raising doubts on to what extent translation can be supra-physiologically stimulated in mammalian cells. In summary, our study provides the first comprehensive characterization of the effect of known drugs on protein translation and has helped to unravel a new link between lipid metabolism and mRNA translation in human cells. mean intensity (a.u.) A B C 2 9 4 6 4 0 n.s.

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Section: Discussionmentioning

confidence: 99%

Section: C) Supporting This View Transition Electron Microscopy (Tmentioning

confidence: 99%

A chemical screen identifies a link between lipid metabolism and mRNA translation

Fernández-Capetillo¹,

Corman

Kanellis

et al. 2020

Preprint

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“…Yeast cells lacking the ORM1 and ORM2 genes show a constitutive unfolded protein response, sensitivity to stress, and slow ER-to-Golgi transport [42]. ORM proteins function as the main regulators of the enzyme serine palmitoyltransferase-necessary for the process of sphingolipid biosynthesis, which is one of the main components of the cytoplasmic membranes of the endoplasmic reticulum, and disturbances in its homeostasis lead to ER stress [43]. The unfolded protein response can also alter sphingolipid metabolism.…”

Section: Upr Inflammation and Cholesterol And Bile Acid Metabolism mentioning

confidence: 99%

“…The unfolded protein response can also alter sphingolipid metabolism. Bi-directional interactions between sphingolipids and the UPR have now been observed in a range of diseases, including cancer, diabetes, and liver disease [43]. Other studies have shown that ER stress can directly initiate the proinflammatory pathways, while proinflammatory agents such as ROS, TLR ligands, and cytokines can induce ER stress.…”

Section: Upr Inflammation and Cholesterol And Bile Acid Metabolism mentioning

confidence: 99%

3′quant mRNA-Seq of Porcine Liver Reveals Alterations in UPR, Acute Phase Response, and Cholesterol and Bile Acid Metabolism in Response to Different Dietary Fats

Oczkowicz

Szmatoła

Świątkiewicz

et al. 2020

Genes

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Animal fats are considered to be unhealthy, in contrast to vegetable fats, which are rich in unsaturated fatty acids. However, the use of some fats, such as coconut oil, is still controversial. In our experiment, we divided experimental animals (domestic pigs) into three groups differing only in the type of fat used in the diet: group R: rapeseed oil (n = 5); group B: beef tallow (n = 5); group C: coconut oil (n = 6). After transcriptomic analysis of liver samples, we identified 188, 93, and 53 DEGs (differentially expressed genes) in R vs. B, R vs. C, and B vs. C comparisons, respectively. Next, we performed a functional analysis of identified DEGs with String and IPA software. We observed the enrichment of genes engaged in the unfolded protein response (UPR) and the acute phase response among genes upregulated in B compared to R. In contrast, cholesterol biosynthesis and cholesterol efflux enrichments were observed among genes downregulated in B when compared to R. Moreover, activation of the UPR and inhibition of the sirtuin signaling pathway were noted in C when compared to R. The most striking difference in liver transcriptomic response between C and B was the activation of the acute phase response and inhibition of bile acid synthesis in the latest group. Our results suggest that excessive consumption of animal fats leads to the activation of a cascade of mutually propelling processes harmful to the liver: inflammation, UPR, and imbalances in the biosynthesis of cholesterol and bile acids via altered organelle membrane composition. Nevertheless, these studies should be extended with analysis at the level of proteins and their function.

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“…These responses include the endoplasmic reticulum stress response and mtUPR [154]. Although it is beyond of the scope of these review, a relevant role of SLs has been reported in endoplasmic reticulum stress response involved in many metabolic and neurodegenerative diseases [155][156][157][158]. mtUPR is evolutionarily conserved and triggers a retrograde signaling pathway from mitochondria to the nucleus leading to the upregulation of chaperones in order to maintain mitochondrial protein homeostasis, when mitochondria have suffered perturbations in protein folding in oxidative phosphorylation or DNA damage.…”

Section: S1p Signaling In Mitochondriamentioning

confidence: 99%

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

Meacci

Garcia‐Gil

2019

IJMS

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The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

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Sphingolipids and the unfolded protein response

Cited by 23 publications

References 103 publications

A chemical screen identifies a link between lipid metabolism and mRNA translation

A chemical screen identifies a link between lipid metabolism and mRNA translation

3′quant mRNA-Seq of Porcine Liver Reveals Alterations in UPR, Acute Phase Response, and Cholesterol and Bile Acid Metabolism in Response to Different Dietary Fats

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

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