Glucosylceramide acyl chain length is sensed by the glycolipid transfer protein

Backman, Anders P. E.; Halin, Josefin; Nurmi, Henrik; Möuts, Anna; Kjellberg, Matti A.; Mattjus, Peter

doi:10.1371/journal.pone.0209230

Cited by 14 publications

(8 citation statements)

References 72 publications

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“…LTPs have been discovered and studied for more than 40 years, yet few studies have explored how their activity depends on the nature of the lipid acyl chains. A few kinetic studies have shown that a nonspecific-LTP transfers shorter PC more easily than long PC [ 50 ], that a glycolipid transfer protein (GLTP) preferentially transports short glucosylceramides [ 51 ] and that the ceramide transfer protein (CERT) is active with ceramide species whose length does not exceed the size of its binding pocket [ 52 , 53 ]. Moreover, the link between the activity of LTPs and their affinity for lipid ligands remained largely obscure.…”

Section: Discussionmentioning

confidence: 99%

Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

et al. 2021

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Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P, and PI(4,5)P2, is critical for maintaining the signaling competence of the cell. Several lipid transfer proteins of the ORP/Osh family contribute to this fine-tuning by delivering PS, synthesized in the endoplasmic reticulum, to the plasma membrane in exchange for PI(4)P. To get insights into the role of these PS/PI(4)P exchangers in regulating plasma membrane features, we question how they selectively recognize and transfer lipid ligands with different acyl chains, whether these proteins exchange PS exclusively for PI(4)P or additionally for PI(4,5)P2, and how sterol abundance in the plasma membrane impacts their activity. Results We measured in vitro how the yeast Osh6p and human ORP8 transported PS and PI(4)P subspecies of diverse length and unsaturation degree between membranes by fluorescence-based assays. We established that the exchange activity of Osh6p and ORP8 strongly depends on whether these ligands are saturated or not, and is high with representative cellular PS and PI(4)P subspecies. Unexpectedly, we found that the speed at which these proteins individually transfer lipid ligands between membranes is inversely related to their affinity for them and that high-affinity ligands must be exchanged to be transferred more rapidly. Next we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for exchange processes, because it is a low-affinity ligand, and do not transfer more PS into sterol-rich membranes. Conclusions Our study provides new insights into PS/PI(4)P exchangers by indicating the degree to which they can regulate the acyl chain composition of the PM, and how they control PM phosphoinositide levels. Moreover, we establish general rules on how the activity of lipid transfer proteins relates to their affinity for ligands.

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Section: Discussionmentioning

confidence: 99%

Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

et al. 2021

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“…In particular, accumulation of short-chain at the expenses of long-chain SL could alter the structural order of membrane lipid bilayers, modify membrane curvature and disrupt membrane fluidity (Niemelä et al, 2006;Ben-David and Futerman, 2010;Mencarelli and Martinez-Martinez, 2013). A switch from long-to short-chain molecules could also interfere with lipid-protein interactions at the plasma membrane level and affect signalling responses involved, for example, in lipid and protein trafficking and degradation and in cell death pathways (Sillence et al, 2002;Kroesen et al, 2003;Koivusalo et al, 2007;Sassa et al, 2012;Ali et al, 2013;Backman et al, 2018). and GBA-mutant mice (Sun et al, 2005;Mazzulli et al, 2011;Sardi et al, 2011;Xu et al, 2011;Cleeter et al, 2013;Schöndorf et al, 2014;Aflaki et al, 2016;Migdalska-Richards et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation

Galvagnion

Cerri

Schapira

et al. 2020

Preprint

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Intraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson’s disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson’s disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein-lipid interactions and the development of Parkinson pathology. In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson’s disease (iPD) and Parkinson patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and iPD cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant change in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter and longer hydrocarbon chain length; levels of shorter-chain molecules were increased while the percent of longer-chain sphingolipids was decreased in PD-GBA lipid extracts. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. In a second set of experiments, lipid extracts from control and PD-GBA fibroblasts were added to incubations of recombinant α-synuclein. The kinetics of α-synuclein aggregation, as assessed by the binding of thioflavin T to amyloid structures, was significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein-lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched of shorter-chain sphingolipids. Taken together, findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile, which includes an increased content of shorter-chain sphingolipids, could also be an indicator of increased risk for α-synuclein aggregate pathology. Shorter-chain molecules may act as preferred reactants during lipid-induced α-synuclein fibrillation.

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“…Depletion of FAPP2 disrupts GlcCer transport from cis- to trans-Golgi, resulting in a disturbed synthesis of complex glycosphingolipids ( D'Angelo et al, 2007 ; D'Angelo et al, 2013 ; Halter et al, 2007 ). How FAPP2 aids in the transport of GlcCer from the cis to the trans-Golgi is not yet fully understood, but may involve ER–Golgi contact sites: FAPP2 has a putative FFAT motif ( Backman et al, 2018 ) and has been suggested to transfer GlcCer retrogradely to the ER, where GlcCer translocates into the lumen. From the ER lumen, GlcCer could be anterogradely transported to the trans-Golgi for further glycosylation into complex glycosphingolipids ( Halter et al, 2007 ).…”

Section: Er-mediated Regulation Of the Golgimentioning

confidence: 99%

ER as master regulator of membrane trafficking and organelle function

Wenzel

Elfmark

Stenmark

et al. 2022

Journal of Cell Biology

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The endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm, is the cell’s main site for the biosynthesis of lipids and carbohydrate conjugates, and it is essential for folding, assembly, and biosynthetic transport of secreted proteins and integral membrane proteins. The discovery of abundant membrane contact sites (MCSs) between the ER and other membrane compartments has revealed that, in addition to its biosynthetic and secretory functions, the ER plays key roles in the regulation of organelle dynamics and functions. In this review, we will discuss how the ER regulates endosomes, lysosomes, autophagosomes, mitochondria, peroxisomes, and the Golgi apparatus via MCSs. Such regulation occurs via lipid and Ca2+ transfer and also via control of in trans dephosphorylation reactions and organelle motility, positioning, fusion, and fission. The diverse controls of other organelles via MCSs manifest the ER as master regulator of organelle biology.

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Glucosylceramide acyl chain length is sensed by the glycolipid transfer protein

Cited by 14 publications

References 72 publications

Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation

ER as master regulator of membrane trafficking and organelle function

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