Regulation of Membrane Turnover by Phosphatidic Acid: Cellular Functions and Disease Implications

Abstract

Phosphatidic acid (PA) is a simple glycerophospholipid with a well-established role as an intermediate in phospholipid biosynthesis. In addition to its role in lipid biosynthesis, PA has been proposed to act as a signaling molecule that modulates several aspects of cell biology including membrane transport. PA can be generated in eukaryotic cells by several enzymes whose activity is regulated in the context of signal transduction and enzymes that can metabolize PA thus terminating its signaling activity have also been described. Further, several studies have identified PA binding proteins and changes in their activity are proposed to be mediators of the signaling activity of this lipid. Together these enzymes and proteins constitute a PA signaling toolkit that mediates the signaling functions of PA in cells. Recently, a number of novel genetic models for the analysis of PA function in vivo and analytical methods to quantify PA levels in cells have been developed and promise to enhance our understanding of PA functions. Studies of several elements of the PA signaling toolkit in a single cell type have been performed and are presented to provide a perspective on our understanding of the biochemical and functional organization of pools of PA in a eukaryotic cell. Finally, we also provide a perspective on the potential role of PA in human disease, synthesizing studies from model organisms, human disease genetics and analysis using recently developed PLD inhibitors.

Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

“…Members of the PKC and Munc13 (mammalian uncoordinated-13) family as well as Ras-GRP4 (Ras guanyl-releasing protein 4) are prime examples of proteins that are regulated by transient changes in DAG [51][52][53]. In principle, conversion of DAG into PA also generates a bioactive metabolite with multiple functions [54][55][56][57][58]. PA can recruit and/or activate specific proteins such as PIP5K [55,56] and, with its cone-shaped geometry, PA can locally influence membrane topology and thus impact in membrane trafficking events [59].…”

Phosphatidic acid in membrane rearrangements

“…However, this substance is present in virtually all cellular membranes ( and references therein). PA is a signalling molecule that regulates several processes in the cell, including cell proliferation, survival, cytoskeletal organization, vesicular trafficking, secretion, reproduction, response to hormones and abiotic stresses . Turnover rate of PA is high , and the cell could regulate the level of PA by the balance of PA synthesis and degradation .…”

“…PA is a signalling molecule that regulates several processes in the cell, including cell proliferation, survival, cytoskeletal organization, vesicular trafficking, secretion, reproduction, response to hormones and abiotic stresses . Turnover rate of PA is high , and the cell could regulate the level of PA by the balance of PA synthesis and degradation . Such regulation has important implication for the cell function and is achieved through the PA‐mediated binding and regulation of a wide range of effector proteins at a certain time and in a particular subcellular membrane region .…”

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

“…In addition to DGKs, various enzymes catalyze the biosynthesis of PA [54]. For example, de novo synthesis through the sequential acylation of G3P and lysophosphatidic acid, which is the main metabolic route catalyzed by lysophosphatidic acid acyltransferase (LPAAT) and phospholipase D (PLD)-catalyzed hydrolysis of PLs, such as phosphatidylcholine (PC) or phosphatidylethanolamine (PE) are shown in Figure 3.…”

“…In addition to DGKs, various enzymes catalyze the biosynthesis of PA [54]. For example, PA is produced from PLD-catalyzed hydrolysis of PLs, such as PC or PE (Figure 3).…”