Structure, functions and regulation of CERT, a lipid‐transfer protein for the delivery of ceramide at the ER–Golgi membrane contact sites

Kumagai, Keigo; Hanada, Kentaro

doi:10.1002/1873-3468.13511

Cited by 92 publications

(70 citation statements)

References 89 publications

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“…The de novo ceramide synthesis pathway is comprised of several enzymes including serine palmitoyltransferase (SPTLC), 3-ketosphinganine reductase (3-KSR), six CerS variants and dihydroceramide desaturase (DES). Ceramide, which is the basic form of SLs, is transported out of the ER, with the transport system including ceramide transfer protein-or vesiclemediated transport system [140,141]. Ceramide can be further metabolized into GSLs and sphingomyelin (SM) by GlcCerase and sphingomyelin synthase (SMS), respectively.…”

Section: Ceramide Synthesis and Degradationmentioning

confidence: 99%

The role of sphingolipids in endoplasmic reticulum stress

Park

2020

FEBS Letters

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The endoplasmic reticulum (ER) is an important intracellular compartment in eukaryotic cells and has diverse functions, including protein synthesis, protein folding, lipid metabolism and calcium homeostasis. ER functions are disrupted by various intracellular and extracellular stimuli that cause ER stress, including the inhibition of glycosylation, disulphide bond reduction, ER calcium store depletion, impaired protein transport to the Golgi, excessive ER protein synthesis, impairment of ER-associated protein degradation and mutated ER protein expression. Distinct ER stress signalling pathways, which are known as the unfolded protein response, are deployed to maintain ER homeostasis, and a failure to reverse ER stress triggers cell death. Sphingolipids are lipids that are structurally characterized by long-chain bases, including sphingosine or dihydrosphingosine (also known as sphinganine). Sphingolipids are bioactive molecules long known to regulate various cellular processes, including cell proliferation, migration, apoptosis and cell-cell interaction. Recent studies have uncovered that specific sphingolipids are involved in ER stress. This review summarizes the roles of sphingolipids in ER stress and human diseases in the context of pathogenic events.

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Section: Ceramide Synthesis and Degradationmentioning

confidence: 99%

The role of sphingolipids in endoplasmic reticulum stress

Park

2020

FEBS Letters

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“…The other key lipid mediator S1P can be produced from ceramide by hydrolysis via ceramidases and subsequent phosphorylation . The intracellular transfer of ceramides is mediated by the ceramide transport protein (CERT), which can transfer ceramides from the endoplasmic reticulum to the trans‐Golgi …”

Section: Diastereomers and Enantiomers Of Ceramide And Sphingosinementioning

confidence: 99%

“…30 The intracellular transfer of ceramides is mediated by the ceramide transport protein (CERT), which can transfer ceramides from the endoplasmic reticulum to the trans-Golgi. 31 Natural ceramide (Cer) and its precursors sphinganine and dihydroceramide exhibit the D-erythro (2S,3R) stereochemistry ( Figure 7). The enantiomer (L-erythro) and one of the diastereomers (L-threo) of natural ceramide and its precursors ( Figure 8) were adopted to examine the ligand stereospecificity of the metabolic enzymes implicated in sphingolipid biosynthesis.…”

Section: Diastereomers and Enantiomers Of Ceramide And Sphingosinementioning

confidence: 99%

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

2020

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Most phospholipids constituting biological membranes are chiral molecules with a hydrophilic head group and hydrophobic alkyl chains, rendering biphasic property characteristic of membrane lipids. Some lipids assemble into small domains via chirality‐dependent homophilic and heterophilic interactions, the latter of which sometimes include cholesterol to form lipid rafts and other microdomains. On the other hand, lipid mediators and hormones derived from chiral lipids are recognized by specific membrane or nuclear receptors to induce downstream signaling. It is crucial to clarify the physicochemical properties of the lipid self‐assembly for the study of the functions and behavior of biological membranes, which often become elusive due to effects of membrane proteins and other biological events. Three major lipids with different skeletal structures were discussed: sphingolipids including ceramides, phosphoglycerolipids, and cholesterol. The physicochemical properties of membranes and physiological functions of lipid enantiomers and diastereomers were described in comparison to natural lipids. When each enantiomer formed a self‐assembly or interacted with achiral lipids, both lipid enantiomers exhibited identical membrane physicochemical properties, while when the enantiomer interacted with chiral lipids or with the opposite enantiomer, mixed membranes exhibited different properties. For example, racemic membranes comprising native sphingomyelin and its antipode exhibited phase segregation due to their strong homophilic interactions. Therefore, lipid enantiomers and diastereomers can be good probes to investigate stereospecific lipid‐lipid and lipid‐protein interactions occurring in biological membranes.

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“…This mechanism highlights the importance of keeping CERT fully active at the ER–TGN contact sites to sustain SM production. An excellent and exhaustive review by Kumagai and Hanada in this issue of FEBS describes all of the features of the CERT protein in detail.…”

Section: Coordination Of Lipid Transfer Activity: the Case Of Certmentioning

confidence: 99%

Illuminating the membrane contact sites between the endoplasmic reticulum and the trans‐Golgi network

2019

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Membrane contact sites (MCSs) between different organelles have been identified and extensively studied over the last decade. Several classes of MCSs have now well‐established roles, although the contacts between the endoplasmic reticulum (ER) and the trans‐side of the Golgi network (TGN) have long remained elusive. Until recently, the study of ER–TGN contact sites has represented a major challenge in the field, as a result of the lack of suitable visualization and isolation techniques. Only in the last 5 years has the combination of advanced technologies and innovative approaches permitted the identification of new molecular players and the functions of ER–TGN MCSs that couple lipid metabolism and anterograde transport. Although much has yet to be discovered, it is now established that ER–TGN MCSs control phosphatidyl‐4‐phosphate homeostasis by coupling the cis and the trans activity of the ER‐resident 4‐phosphatase Sac1. In this review, we focus on recent advances on the composition and function of ER–TGN MCSs.

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Structure, functions and regulation of CERT, a lipid‐transfer protein for the delivery of ceramide at the ER–Golgi membrane contact sites

Cited by 92 publications

References 89 publications

The role of sphingolipids in endoplasmic reticulum stress

The role of sphingolipids in endoplasmic reticulum stress

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

Illuminating the membrane contact sites between the endoplasmic reticulum and the trans‐Golgi network

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