Emerging perspectives on multidomain phosphatidylinositol transfer proteins

Raghu, Padinjat; Basak, Bishal; Krishnan, Harini

doi:10.1016/j.bbalip.2021.158984

Cited by 12 publications

(8 citation statements)

References 86 publications

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“…45 The ability to bind multiple ligands, as observed in STARD3, is a relatively common feature of lipid transporters. [46][47][48][49] Lipid exchangers use this property to transport sterols or phosphatidylserine against their concentration gradient, taking advantage of the hydrolysis of counter-transported lipids such as phosphoinositides. 48,[50][51][52] Whether STARD3 also utilizes such a counter-transport mechanism is not clear for now.…”

Section: Discussionmentioning

confidence: 99%

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

Hempelmann,

Lolicato,

Graziadei

et al. 2023

Preprint

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Sphingolipids are important structural components of membranes. Additionally, simple sphingolipids such as sphingosine are highly bioactive and participate in complex subcellular signaling. Sphingolipid deregulation is associated with many severe diseases including diabetes, Parkinson's and cancer. Here, we focus on how sphingosine, generated from sphingolipid catabolism in late endosomes/lysosomes, is reintegrated into the biosynthetic machinery at the endoplasmic reticulum (ER). We characterized the sterol transporter STARD3 as a sphingosine transporter acting at lysosome-ER contact sites. Experiments featuring crosslinkable sphingosine probes, supported by unbiased molecular dynamics simulations, exposed how sphingosine binds to the lipid-binding domain of STARD3. Following the metabolic fate of pre-localized lysosomal sphingosine showed the importance of STARD3 and its actions at contact sites for the integration of sphingosine into ceramide in a cellular context. Our findings provide the first example of inter-organellar sphingosine transfer and pave the way for a better understanding of sphingolipid - sterol co-regulation.

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Section: Discussionmentioning

confidence: 99%

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

Hempelmann,

Lolicato,

Graziadei

et al. 2023

Preprint

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“…We found that PNUT shows a concentration-dependent binding to PI(4,5)P 2 (Fig 4I). Thus, PNUT PNUT regulates PI(4,5)P 2 synthesis via dPIP5K L and downstream of RDGB function During PLCβ signalling in Drosophila photoreceptors, PI(4,5)P 2 is replenished through the sequential phosphorylation of PI by PI4KIIIα (Balakrishnan et al, 2018) and dPIP5K (Chakrabarti et al, 2015); the PI required as substrate is provided at the plasma membrane by the lipid transfer protein RDGB (Yadav et al, 2015;Raghu et al, 2021). To uncover the step of the phototransduction cycle that could be regulated by PNUT, we tested the effect of PNUT depletion in photoreceptors that were also depleted for RDGB.…”

Section: Dpip5k L Is Essential For Normal Phototransductionmentioning

confidence: 99%

Septins tune lipid kinase activity and PI(4,5)P₂ turnover during G-protein–coupled PLC signalling in vivo

et al. 2022

Self Cite

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Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] hydrolysis by phospholipase C (PLC) is a conserved mechanism of signalling. Given the low abundance of PI(4,5)P2, its hydrolysis needs to be coupled to resynthesis to ensure continued PLC activity; however, the mechanism by which depletion is coupled to resynthesis remains unknown. PI(4,5)P2 synthesis is catalyzed by the phosphorylation of phosphatidylinositol 4 phosphate (PI4P) by phosphatidylinositol 4 phosphate 5 kinase (PIP5K). In Drosophila photoreceptors, photon absorption is transduced into PLC activity and during this process, PI(4,5)P2 is resynthesized by a PIP5K. However, the mechanism by which PIP5K activity is coupled to PI(4,5)P2 hydrolysis is unknown. In this study, we identify a unique isoform dPIP5KL, that is both necessary and sufficient to mediate PI(4,5)P2 synthesis during phototransduction. Depletion of PNUT, a non-redundant subunit of the septin family, enhances dPIP5KL activity in vitro and PI(4,5)P2 resynthesis in vivo; co-depletion of dPIP5KL reverses the enhanced rate of PI(4,5)P2 resynthesis in vivo. Thus, our work defines a septin-mediated mechanism through which PIP5K activity is coupled to PLC-mediated PI(4,5)P2 hydrolysis.

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“…Subsequently, CDP-DAG is converted into phosphatidylinositol (PI), which is transferred back to the microvillar membrane, by the PI transfer protein (PITP), encoded by the retinal degeneration B (rdgB gene [56]) located to the SMC. This mutant was discovered as a mutant causing rapid light-induced retinal degeneration [57][58][59]. PIP and PIP 2 are produced at the microvillar membrane by PI kinase and PIP kinase, respectively.…”

Section: Evidence For Lipids Action As Second Messengersmentioning

confidence: 99%

The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels

Gutorov¹,

Katz²,

Rhodes-Mordov³

et al. 2022

Biomolecules

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Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase Cβ (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Diacylglycerol (DAG) and Inositol 1, 4,5-trisphosphate (IP3). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP2 depletion or IP3-mediated Ca2+ release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the Drosophila TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP2 into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of Drosophila TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions.

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Emerging perspectives on multidomain phosphatidylinositol transfer proteins

Cited by 12 publications

References 86 publications

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

Septins tune lipid kinase activity and PI(4,5)P₂ turnover during G-protein–coupled PLC signalling in vivo

The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels

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Emerging perspectives on multidomain phosphatidylinositol transfer proteins

Cited by 12 publications

References 86 publications

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

Septins tune lipid kinase activity and PI(4,5)P2 turnover during G-protein–coupled PLC signalling in vivo

The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels

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Septins tune lipid kinase activity and PI(4,5)P₂ turnover during G-protein–coupled PLC signalling in vivo