Role of Phospholipase D-Derived Phosphatidic Acid in Regulated Exocytosis and Neurological Disease

Tanguy, Emeline; Wang, Qili; Vitale, Nicolas

doi:10.1007/164_2018_180

Cited by 17 publications

(12 citation statements)

References 98 publications

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“…We also observed an enrichment of PA at WPB-PM fusion sites in histamine-evoked VWF exocytosis. As shown in other systems, an accumulation of PA in the inner cytosolic leaflet of vesicle-PM contact sites facilitates membrane curvatures that support fusion (Bullen & Soldati-Favre, 2016;Tanguy et al, 2018). In addition, PA could act by recruiting proteins mediating evoked WPB exocytosis.…”

Section: Discussionmentioning

confidence: 76%

Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis

2020

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Weibel–Palade bodies (WPB) are specialized secretory organelles of endothelial cells that control vascular hemostasis by regulated, Ca2+-dependent exocytosis of the coagulation-promoting von-Willebrand factor. Some proteins of the WPB docking and fusion machinery have been identified but a role of membrane lipids in regulated WPB exocytosis has so far remained elusive. We show here that the plasma membrane phospholipid composition affects Ca2+-dependent WPB exocytosis and von-Willebrand factor release. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] becomes enriched at WPB–plasma membrane contact sites at the time of fusion, most likely downstream of phospholipase D1-mediated production of phosphatidic acid (PA) that activates phosphatidylinositol 4-phosphate (PI4P) 5-kinase γ. Depletion of plasma membrane PI(4,5)P2 or down-regulation of PI4P 5-kinase γ interferes with histamine-evoked and Ca2+-dependent WPB exocytosis and a mutant PI4P 5-kinase γ incapable of binding PA affects WPB exocytosis in a dominant-negative manner. This indicates that a unique PI(4,5)P2-rich environment in the plasma membrane governs WPB fusion possibly by providing interaction sites for WPB-associated docking factors.

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Section: Discussionmentioning

confidence: 76%

Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis

2020

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“…Two effects on secretion are generally discussed, firstly, that it could serve as a landmark in the plasma membrane, labelling the sites of exocytosis and recruiting proteins required for secretory processes. In this context, the anionic charge of its headgroup might help PA to interact with the positively charged domain of interacting proteins [ 272 , 274 ]. In line with this hypothesis, components of the tobacco exocyst complex partially colocalise with PA sensors in tobacco pollen tubes [ 215 ].…”

Section: Phospholipase D-produced Phosphatidic Acid Regulates Polmentioning

confidence: 99%

Signalling Pinpointed to the Tip: The Complex Regulatory Network That Allows Pollen Tube Growth

Scholz¹,

Anstatt²,

Krawczyk³

et al. 2020

Plants

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Plants display a complex life cycle, alternating between haploid and diploid generations. During fertilisation, the haploid sperm cells are delivered to the female gametophyte by pollen tubes, specialised structures elongating by tip growth, which is based on an equilibrium between cell wall-reinforcing processes and turgor-driven expansion. One important factor of this equilibrium is the rate of pectin secretion mediated and regulated by factors including the exocyst complex and small G proteins. Critically important are also non-proteinaceous molecules comprising protons, calcium ions, reactive oxygen species (ROS), and signalling lipids. Among the latter, phosphatidylinositol 4,5-bisphosphate and the kinases involved in its formation have been assigned important functions. The negatively charged headgroup of this lipid serves as an interaction point at the apical plasma membrane for partners such as the exocyst complex, thereby polarising the cell and its secretion processes. Another important signalling lipid is phosphatidic acid (PA), that can either be formed by the combination of phospholipases C and diacylglycerol kinases or by phospholipases D. It further fine-tunes pollen tube growth, for example by regulating ROS formation. How the individual signalling cues are intertwined or how external guidance cues are integrated to facilitate directional growth remain open questions.

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“…1a ). PLD-generated PA regulates a multitude of cellular processes including activation of mTOR and MAPK pathways, vesicular trafficking and endocytosis, membrane fission and fusion, and cell growth, proliferation, and migration 1 – 3 .…”

Section: Introductionmentioning

confidence: 99%

“…PLD has been identified as a therapeutic target for several diseases 4 , including most prominently cancer 5 , 6 , but also autoimmune 7 , 8 , neurodegenerative 3 , 9 , and cardiovascular disease 10 . Potent and specific small molecule inhibitors have been developed 11 – 13 and pharmacological inhibition is effective in preventing cancer cell invasion in cell culture 6 , neoangiogenesis and metastasis 5 , and thrombosis 14 .…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA

et al. 2020

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The signal transduction enzyme phospholipase D1 (PLD1) hydrolyzes phosphatidylcholine to generate the lipid second-messenger phosphatidic acid, which plays roles in disease processes such as thrombosis and cancer. PLD1 is directly and synergistically regulated by Protein Kinase C, Arf and Rho GTPases, and the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP 2 ). Here, we present a 1.8Å-resolution crystal structure of the human PLD1 catalytic domain that is characterized by a globular fold with a funnel-shaped hydrophobic cavity leading to the active site. Adjacent is a PIP 2 -binding polybasic pocket at the membrane interface that is essential for activity. The C-terminus folds into and contributes part of the catalytic pocket, which harbors a phosphohistidine that mimics an intermediate stage of the catalytic cycle. Mapping of PLD1 mutations that disrupt RhoA activation identifies the RhoA-PLD1 binding interface. This structure sheds light on PLD1 regulation by lipid and protein effectors, enabling rationale inhibitor design for this well-studied therapeutic target.

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Role of Phospholipase D-Derived Phosphatidic Acid in Regulated Exocytosis and Neurological Disease

Cited by 17 publications

References 98 publications

Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis

Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis

Signalling Pinpointed to the Tip: The Complex Regulatory Network That Allows Pollen Tube Growth

Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA

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