Abstract

Lipids function not only as the major structural components of cell membranes, but also as molecular messengers that transduce signals to trigger downstream signaling events in the cell. Phosphatidic acid (PA), the simplest and a minor class of glycerophospholipids, is a key intermediate for the synthesis of membrane and storage lipids, and also plays important roles in mediating diverse cellular and physiological processes in eukaryotes ranging from microbes to mammals and higher plants. PA comprises different molecular species that can act differently, and is found in virtually all organisms, tissues, and organellar membranes, with variations in total content and molecular species composition. The cellular levels of PA are highly dynamic in response to stimuli and multiple enzymatic reactions can mediate its production and degradation. Moreover, its unique physicochemical properties compared with other glycerophospholipids allow PA to influence membrane structure and dynamics, and interact with various proteins. PA has emerged as a class of new lipid mediators modulating various signaling and cellular processes via its versatile effects, such as membrane tethering, conformational changes, and enzymatic activities of target proteins, and vesicular trafficking.

Introduction

Membrane lipids encompass various types of lipids with distinct properties and functions, and play the primary role in forming a barrier to compartmentalize the whole cell and membrane-bound organelles found inside eukaryotic cells. The structural role of membrane lipids stems from their intrinsic amphipathic nature due to the polar head group and nonpolar hydrocarbon tails, forming the lipid bilayer. Glycerophospholipids, also known as phosphoglycerides or simply phospholipids, account for over 60% of total membrane lipids found in most types of cells [1,2]. They are composed of a three-carbon glycerol backbone linked by ester bonds with a phosphate group as the polar head group and two, or one in much less frequency, fatty acids as the nonpolar tails (Figure 1). The fatty acids can differ in both length (normally 14–24 carbon atoms) and the degree of unsaturation (1–4 double bonds). The phosphate group is often found as being di-esterified with a small alcohol molecule, such as choline, ethanolamine, inositol, and serine, from which the phospholipids are named with a prefix ‘phosphatidyl’ or ‘Ptd’ (e.g. phosphatidylcholine [PtdCho; PC], phosphatidylethanolamine [PtdEtn; PE], etc.). Among glycerophospholipids, phosphatidic acid (PtdOH; PA) is smallest in head group size, which has a mono-esterified phosphate with no alcohol group (Figure 1).

PA metabolism

Figure 1
PA metabolism

Molecular structure is schematically shown to help distinguish chemical groups (see the box legend). The carbonyl group (O =) in DHAP denotes the acetone backbone. Dashed arrow represents multistep conversion. Abbreviations: CDS, cytidyldiphosphate-diacylglycerol synthase; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; DHAP-AT, DHAP acyltransferase; DGK, DAG kinase; DGPP, DAG pyrophosphate; LPA, lysophosphatidic acid; PA, phosphatidic acid; GPAT, G3P acyltransferase; G3P, glycerol 3-phosphate; LPAAT, LPA acyltransferase; LPP, lipid phosphate phosphatase; NPC, nonspecific PLC; PAK, PA kinase; PAP, PA phosphatase; PL, phospholipid; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D.

Figure 1
PA metabolism

Molecular structure is schematically shown to help distinguish chemical groups (see the box legend). The carbonyl group (O =) in DHAP denotes the acetone backbone. Dashed arrow represents multistep conversion. Abbreviations: CDS, cytidyldiphosphate-diacylglycerol synthase; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; DHAP-AT, DHAP acyltransferase; DGK, DAG kinase; DGPP, DAG pyrophosphate; LPA, lysophosphatidic acid; PA, phosphatidic acid; GPAT, G3P acyltransferase; G3P, glycerol 3-phosphate; LPAAT, LPA acyltransferase; LPP, lipid phosphate phosphatase; NPC, nonspecific PLC; PAK, PA kinase; PAP, PA phosphatase; PL, phospholipid; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D.

Besides being vital structural components of cell membranes, some membrane lipids also act to transduce cellular signals to trigger intracellular signaling events. Signaling lipids often exist in a small quantity and are rapidly and transiently produced in response to stimuli to activate, or inactivate, their downstream targets. PA had long been regarded as a transiently occurring metabolic intermediate that was produced for membrane and storage lipid biosynthesis and from the breakdown of major membrane phospholipids. However, a growing body of recent evidence has positioned PA as a novel messenger that mediates a wide variety of biological processes in various organisms. The cellular and signaling functions of PA have been extensively described [3–11]. This review will focus on what makes PA such a versatile class of cellular mediators and how it affects downstream targets.

Molecular structure of PA

Designation of PA structure

PA is a class of glycerophospholipids with diacyl glycerophosphate. In glycerophospholipids, the three carbons in the glycerol backbone are numbered based on the stereospecific numbering (sn) system [12]. Thus, all PA molecules have a fatty acid at each of sn-1 and sn-2 positions and a phosphate group at sn-3 position of the glycerol backbone, designated as 1,2-diacyl-sn-glycero-3-phosphate (Figure 1). According to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature of fatty acids, PA, for example, with C16:0 (16 carbons and no double bond) at sn-1 position and C18:1 (18 carbons and one double bond at the Δ-9 position in oleic acid) at sn-2 position is designated fully as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate, or shortly and more commonly as 16:0-18:1PA. Its molecular formula is C37H70O8P, and has a molecular mass of 696.

Molecular species of PA and signaling implications

PA comprises various individual molecules, called ‘molecular species’, because the two fatty acyl groups can differ in the number of carbons and double bonds. Often, PA species are presented as ‘the total number of carbons : double bonds of two acyl chains’, such as 34:2PA, when the two acyl groups have not been identified [13]. Compositions of PA species differ among organisms. In leaves of the model plant Arabidopsis (Arabidopsis thaliana), 34:2PA is most abundant, followed by 34:3PA, 36:4PA, and 36:5PA. The relative abundance of major PA species is largely similar among different Arabidopsis tissues and in leaves and roots of soybean (Glycine max), with 36:2PA, 36:3PA, and 36:6PA substantially found in soybean tissues [14,15]. The number of PA species and their relative quantity found in animals differ from those in plants, primarily due to the polyunsaturated fatty acids (e.g. C20:4 and C22:6) abundant in animal cells. In mouse brain tissue, the level of 34:1PA is remarkably high and relatively abundant species include 36:1PA, 38:4PA, and 36:2PA [16]. Yeast (Saccharomyces cerevisiae) displays a much simpler fatty acid composition of PA. It has only C16 and C18 with no or one double bond, and is relatively rich in 32:2PA and 34:2PA [17,18]. In Escherichia coli, PA species are abundant in the order of 32:1PA, 34:1PA = 34:2PA and 30:0PA [19].

Recent results have shown that the cellular levels of different PA species respond differently to stimuli, such as photoperiod. Levels of PA species, such as 34:3PA and 36:5PA, changed in day/night cycle and 34:4PA and 36:6PA underwent a circadian oscillation in Arabidopsis [20,21]. 18:0-20:4PA, 16:0-18:2PA, and 16:0-18:1PA also oscillated diurnally in the nucleus of mouse liver cells, with 16:0-18:1PA oscillating in mitochondria as well [22]. Moreover, different PA species have been found to interact with different proteins, suggesting that they have distinct biological activities [21,23–26]. This is also supported by the observation that among phospholipid classes, PA displays the most varied species compositions among different organs of Arabidopsis [14], probably due to the diversity of PA-metabolizing enzymes as described below, signifying tissue-specific activities of different PA species.

PA metabolism and distribution

Synthesis and degradation pathways

PA can be produced by multiple enzymatic reactions, such as acylation, phosphorylation, and hydrolysis (Figure 1). In the de novo pathway, PA is synthesized by two sequential acylation of glycerol 3-phosphate (G3P) or dihydroxyacetone phosphate (DHAP), an intermediate of the glycolysis, by G3P acyltransferase and DHAP acyltransferase, respectively [6,27]. The resulting lysophosphatidic acid (LPA) undergoes the second acylation catalyzed by LPA acyltransferase to become PA [28]. In addition, the breakdown of major membrane phospholipids, including PC and PE, can directly generate PA and this hydrolysis reaction is catalyzed by phospholipase D (PLD) [3]. PA also can be formed via phosphorylation of diacylglycerol (DAG) by DAGkinase (DGK) or dephosphorylation of DAGpyrophosphate (DGPP) by lipid phosphate phosphatase (LPP). Moreover, DAG is produced from hydrolysis of phosphoinositides by phospholipase C (PLC) and from common phospholipids in plants and bacteria by nonspecific PLC (NPC). The activities of PLC/NPC followed by DGK contribute to PA production. Traditionally, while the de novo pathway has been regarded to contribute to the formation of structural PA as a precursor for the synthesis of other glycerolipids, the PLD, DGK, and LPP pathways are thought to be responsible for signaling PA production. However, increasing evidence suggests the functional cross-talk and thus an ambiguous boundary between the different PA pools. PA is removed by dephosphorylation to DAG by PAphosphohydrolase (PAP) [29], deacylation to LPA by phospholipase A, or even further phosphorylation to DGPP by PA kinase [30,31]. In addition, cytidyldiphosphate (CDP)-DAG synthase converts PA into CDP-DAG for the synthesis of phospholipids, such as phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol [32].

In addition, since both PA and DAG are important lipid mediators and have distinct effects, the interconversion between them, mediated mainly by the activities of DGK, PAP, and LPP (Figure 1), plays important roles in cell regulation. The homeostasis of cellular PA and DAG levels is involved in different processes, such as membrane trafficking, cell proliferation and motility, immune responses, and glucose metabolism [33–35]. Furthermore, PA acts as a mediator regulating glycerolipid metabolism. In yeast, PA has been shown to act as a key feedback regulator through interacting with a transcriptional repressor overproduction of inositol 1 protein (Opi1p) for the expression of some phospholipid synthesis genes, including the ones encoding PA metabolic enzymes described above [36–38]. In Arabidopsis, PA interacts with a transcription factor to promote triacylgylcerol catabolism during seed germination and seedling growth [39]. Thus, the synthesis and degradation of PA are regulated, in part, by cellular levels of PA itself for lipid homeostasis.

Dynamics of cellular PA content

In response to stimuli, such as hormones, abiotic and biotic stress conditions, the cellular levels of PA increase by several to over ten-fold rapidly and transiently [40]. The stimulus-induced production of PA is mediated by one or more enzymatic reactions, such as the ones catalyzed by PLD and/or PLC coupled with DGK, depending on the type of stimulation (Figure 1). In addition, each family of these enzymes has multiple members and for example, individual PLDs of 12 isoforms in Arabidopsis can be induced differently in response to different stimuli, such as dehydration, high salinity, phosphorus or nitrogen deficiencies, oxidative stress, and pathogens [3,4]. Some of these enzymes among different families of the enzymes and different members of the same family display different substrate preferences, intracellular distribution, acyl chain preferences, and expression patterns in responses to stimuli [4]. These differences account for the heterogeneity and highly dynamic nature of PA contents and compositions in organs, tissues, and organelles. Recently, PA biosensors have provided real-time measure of PA dynamics in response to stimuli, such as treatments of NaCl, abscisic acid, and pH change in Arabidopsis [41], and have shown colocalization with PA-producing enzymes, such as PLD and DGK, at the plasma membrane and Golgi apparatus in CV-1 in Origin Simian-7 (COS-7) cells [42].

Organ/tissue distribution

PA contents vary among different organs or tissues, but their physiological significance is only speculative at the moment. In Arabidopsis, the level of PA in roots is, in general, higher than that of leaves (over three-fold, depending on experimental conditions) [14,43–45], and PA has been implicated in maintaining root architecture [46]. Another study has revealed that mature flowers of wild-type Arabidopsis contain a large quantity of PA (∼7 nmol/mg dry weight), and that the PA level is as high as the most abundant phospholipid PC in floral homeotic mutants rich in specific floral organs [47]. The high level of PA in reproductive organs relative to other tissues is also observed in Petunia hybrida (11–15 mol% in floral organs vs. ∼1% in leaf) [48], but its significance is unknown. Both PA and several PA-binding proteins of unknown function have been found in the exudates of Arabidopsis phloem (vascular tissue to transport soluble organic compounds) [49,50]. This raises the possibility of inter-organ transfer of PA with proteins bound, and suggests that PA may also play a role in long-distance signaling. PA accounts for ∼37 mol% of total phospholipids in a yeast strain Saccharomyces kudriavzevii [51]. In mammals, ∼60 nmol/g fresh weight of PA has been detected in mouse brain tissue, which is ∼30-times more than found in heart [52]. Rats have PA contents of ∼5.4 weight% of total phospholipids in lung, 4.3% in heart, and below 2% in liver and kidney [53]. It is worth noting that accurate PA measurements require precaution to minimize the rapid activation of highly sensitive lipolytic enzymes (e.g. PLD) during the sample preparation [13]. Thus, data interpretation would need to be limited to relative PA levels among organs/tissues treated with the same extent of precaution in parallel.

Intracellular distribution

The eukaryotic and unicellular nature of yeasts facilitates studies of the intracellular distribution of lipids. PA accounts for ∼3% of total glycerophospholipids in yeast (S. cerevisiae), of which 32:1PA and 34:2PA are in the plasma membrane and 32:1PA is also in the nucleus [54]. A more comprehensive study with the same strain has indicated that PA contents are 4.4 mol% in the outer mitochondrial membrane, 3.9% in the plasma membrane, 2.4% in mitochondria, and 2% in the nucleus and vacuoles [55]. Despite the low abundance in the nucleus and vacuoles, PA is known to be essential to the vacuolar fusion process and the formation of ‘prospore’ membrane around each haploid nucleus during yeast sporulation [56–58]. Mung bean hypocotyls have PA contents of 16.3 mol% of phospholipids in the plasma membrane, but only 2.1% in tonoplasts [59]. It should be noted that the study of intracellular distribution of PA is technically challenging, again due to the high lipolytic activity, particularly PLD, in plants. Arabidopsis PLDs require Ca2+ for their activity, and inclusion of a metal chelator, such as ethyleneglycol tetraacetic acid (EGTA), in the buffers used for organelle isolation has been proven to effectively inhibit the lipolytic activity [39].

The intracellular distribution of PA-metabolizing enzymes provides valuable insights about the subcellular occurrence and function of PA. Activity assay and immunoblotting analysis with fractionated Arabidopsis leaf cells have revealed two PLD isoforms PLDα and PLDγ present in the plasma membrane, intracellular membranes, mitochondria, and clathrin-coated vesicles, with PLDγ also found in the nucleus [60]. Nuclear functions of PA have been proposed by recent studies demonstrating PA-dependent nuclear processes, such as protein nuclear translocation, transcriptional regulation, and DNA replication [21,39,61,62]. In addition to PLDγ, some isoforms of DGK and PAP are localized in the nucleus in both plants and animals [63–65]. A PLD family member, MitoPLD was found on the mitochondrial surface in mouse [66]. MitoPLD-generated PA regulates mitochondrial dynamics via membrane fusion/fission processes, and is required for the progression of spermatogenesis for male fertility [67,68].

PA transfer between organelles

Dynamic changes of intracellular PA distribution under various cellular conditions are attributed to its inter-organelle transfer via vesicular transport, described in a later section, and at the membrane contact sites (MCSs) by lipid transfer proteins, as well as the on-site production by PA-producing enzymes. PA transfer from the plasma membrane to the endoplasmic reticulum (ER) at MCS is mediated by retinal degeneration-type B (RdgB) in fly photoreceptors and its human homolog, PYK2 N-terminal domain-interacting receptor 2 (Nir2), and be crucial for the resynthesis of phosphatidylinositol 4,5-bisphosphate consumed in the PLC and Ca2+ signaling [69,70]. PA is transferred from ER to mitochondrial outer membrane (MOM) by a protein complex known as ER-mitochondria encounter structure (ERMES), which is located at the ER-mitochondria contact site, and then to mitochondrial inner membrane (MIM) by Usp1-Mdm35 (mitochondria distribution and morphology 35) at the MOM-MIM contact site for the synthesis of MIM-enriched lipid cardiolipin [71]. A similar mechanism has been proposed for PA transport from ER to chloroplasts in plants, which is mediated by trigalactosyl–DAG (TGD) protein complexes presumably located at the MCS between ER and chloroplasts and between chloroplast outer and inner membranes [72,73]. The inter-organelle transfer of PA via the MCS and vesicular trafficking would rapidly supply the indispensable lipid to the organelles lacking PA-producing enzymes to mediate cellular functions.

PA interaction with proteins

PA interactions with proteins play a key role in its signaling and cellular functions. A number of proteins have been identified to physically bind and/or be regulated by PA, and lists of PA-binding proteins described earlier are provided elsewhere, along with their properties affected by PA and physiological relevance of the interaction [3,4,7,8,11,74]. The number of potential downstream effectors of PA is increasing, and Table 1 shows the PA-interacting proteins that have been recently identified and cellular processes involved. Below, we briefly describe the physicochemical properties of PA involved in its interaction with proteins, common methods to examine PA–protein interaction, and its direct effects on the proteins per se, rather than detailed cellular or physiological consequences.

Table 1
Recently identified PA-interacting proteins
ProteinProtein functionPA effect on the proteinOrganismReference
LATS Activated by MOB1 and phosphorylates YAP/TAZ in Hippo pathway Inhibits binding to MOB1 Human [75
NF2 Recruits LATS to plasma membrane in Hippo pathway Inhibits binding to LATS Human [75
Sec18p Binds to and activates cis-SNAREs for vacuole fusion Inhibits binding to cis-SNAREs Yeast [76,77
VapA Virulence determinant of Rhodococcus equi for macrophage infection Unknown Bacteria (R. equi[78
LHY/CCA1 Transcription factor to regulate rhythmic gene expression for circadian clock Inhibits binding to target promoter Arabidopsis [21
AHL4 Transcriptional factor to regulate TAG degradation for seeding establishment Inhibits binding to target promoter Arabidopsis [39
SEIPIN ER membrane protein important to lipid droplet formation Unknown Human [79
ERK3 Phosphorylates and activates Rac1–PAK complex for cell migration Stimulates ERK3 phosphorylation Human [80,81
LDHA Converts pyruvate into lactate for anaerobic glycolysis Unknown Mouse [24
α-Synuclein Unknown; associated with Parkinson’s disease Promotes secondary structural change and aggregation Human [42,82
AKT2 Potassium channel to stabilize membrane potentials Inhibits channel activity Rice [83
MKK7/9 Phosphorylates and activates MPK6 in salt stress signaling Increases kinase activity and plasma membrane localization Arabidopsis [84
TIM Unclear; membrane protein family for immune response Enhances binding to PS on membrane Human [85
CKM Converts creatine into phosphocreatine for energy metabolism Unknown Mouse [86
PP2CA Regulates ABA signaling for stomatal movement Inhibits phosphatase activity Arabidopsis [87
TREK-1 Potassium channel for resting membrane potential Stimulates channel activity Drosophila [88
RA-GEF-1/2 Guanine nucleotide exchange factor to activate Rap1 for lymphocyte migration Induces plasma membrane localization Human [89
SNX1 Promotes vacuolar degradation of PIN2 for root hair development Induces plasma membrane localization Arabidopsis [90
CgA Promotes secretory granule formation at trans-Golgi network Induces membrane deformation and remodeling Mouse [91
Praja-1 E3 ubiquitin ligase to degrade SERT for serotonin transport Increases enzyme activity Mouse [92
MiD51 Recruits Drp1 to mitochondrial outer membrane for mitochondrial fission Promotes secondary structural change Unknown [93
Chm7 Nuclear protein for nuclear pore complex assembly and nuclear membrane remodeling Promotes localization to inner nuclear membrane Yeast [94
ProteinProtein functionPA effect on the proteinOrganismReference
LATS Activated by MOB1 and phosphorylates YAP/TAZ in Hippo pathway Inhibits binding to MOB1 Human [75
NF2 Recruits LATS to plasma membrane in Hippo pathway Inhibits binding to LATS Human [75
Sec18p Binds to and activates cis-SNAREs for vacuole fusion Inhibits binding to cis-SNAREs Yeast [76,77
VapA Virulence determinant of Rhodococcus equi for macrophage infection Unknown Bacteria (R. equi[78
LHY/CCA1 Transcription factor to regulate rhythmic gene expression for circadian clock Inhibits binding to target promoter Arabidopsis [21
AHL4 Transcriptional factor to regulate TAG degradation for seeding establishment Inhibits binding to target promoter Arabidopsis [39
SEIPIN ER membrane protein important to lipid droplet formation Unknown Human [79
ERK3 Phosphorylates and activates Rac1–PAK complex for cell migration Stimulates ERK3 phosphorylation Human [80,81
LDHA Converts pyruvate into lactate for anaerobic glycolysis Unknown Mouse [24
α-Synuclein Unknown; associated with Parkinson’s disease Promotes secondary structural change and aggregation Human [42,82
AKT2 Potassium channel to stabilize membrane potentials Inhibits channel activity Rice [83
MKK7/9 Phosphorylates and activates MPK6 in salt stress signaling Increases kinase activity and plasma membrane localization Arabidopsis [84
TIM Unclear; membrane protein family for immune response Enhances binding to PS on membrane Human [85
CKM Converts creatine into phosphocreatine for energy metabolism Unknown Mouse [86
PP2CA Regulates ABA signaling for stomatal movement Inhibits phosphatase activity Arabidopsis [87
TREK-1 Potassium channel for resting membrane potential Stimulates channel activity Drosophila [88
RA-GEF-1/2 Guanine nucleotide exchange factor to activate Rap1 for lymphocyte migration Induces plasma membrane localization Human [89
SNX1 Promotes vacuolar degradation of PIN2 for root hair development Induces plasma membrane localization Arabidopsis [90
CgA Promotes secretory granule formation at trans-Golgi network Induces membrane deformation and remodeling Mouse [91
Praja-1 E3 ubiquitin ligase to degrade SERT for serotonin transport Increases enzyme activity Mouse [92
MiD51 Recruits Drp1 to mitochondrial outer membrane for mitochondrial fission Promotes secondary structural change Unknown [93
Chm7 Nuclear protein for nuclear pore complex assembly and nuclear membrane remodeling Promotes localization to inner nuclear membrane Yeast [94

Physicochemical properties of PA and the pH effect

Due to its small head group and relatively bulky fatty acid chains, PA has an overall cone-like molecular shape, rather than the cylindrical shape typical of other glycerophospholipids [95,96]. This structural property of PA impedes tight packing of the lipid bilayer by slightly exposing hydrophobic interior around PA molecules, which attracts hydrophobic residues in proteins (Figure 2, top). At physiological pH the phosphomonoester group of PA forms intramolecular hydrogen bond between its two hydroxyl groups, causing the PA molecule to have a net charge of −1. However, the head group can be deprotonated by intermolecular hydrogen bonds formed with a positively charged amino acid (e.g. lysine or arginine) in proteins. This increases the net charge of PA to −2, and thus stabilizes the lipid–protein interaction via electrostatic attraction with a stretch of basic residues found in many PA-binding proteins [97–99]. Together with the cone-shaped structure of PA, this so-called ‘electrostatic/hydrogen bond switch mechanisms’ explains the strong and specific interaction of proteins with PA over other anionic phospholipids [11]. In addition, the pH-sensitive (de)protonation states affect PA’s ability to interact with proteins, and PA is regarded as a pH sensor in yeast response to nutrients and plant response to salt stress [41,100].

Biochemical effects of PA on target proteins

Figure 2
Biochemical effects of PA on target proteins

PA binding can tether soluble proteins to membranes, induce conformational changes, hinder ligand binding, and/or oligomerize, thus to alter various properties of the proteins, including catalytic activity, protein stability, and interaction with other molecules. Note that PA may have multiple effects on a single protein (e.g. simultaneous membrane tethering and conformational change).

Figure 2
Biochemical effects of PA on target proteins

PA binding can tether soluble proteins to membranes, induce conformational changes, hinder ligand binding, and/or oligomerize, thus to alter various properties of the proteins, including catalytic activity, protein stability, and interaction with other molecules. Note that PA may have multiple effects on a single protein (e.g. simultaneous membrane tethering and conformational change).

Methods to examine PA–protein interaction

Various protein sources, such as a soluble protein extract, membrane proteins, and a library of transcription factors, have been screened for proteomic identification of novel PA-binding proteins by a number of techniques that are also used complementarily for subsequent verification and quantification of the PA–protein interaction [5,21,26,101,102]. One way to study PA–protein interaction is protein-lipid overlay assay, also known as ‘fat-Western blot’ or ‘filter-blotting assay’ that is named literally from the immunodetection of proteins blotted on a PA-immobilized filter. It is easy and fast, but results obtained from this method may not correctly reflect what would occur in real biological membranes. In another technique, called ‘liposome co-precipitation’, proteins are co-precipitated with insoluble lipid vesicles (‘liposomes’) composed of PA-containing lipid bilayers, and are detected by immunoblotting. It is usually preferred due to the compositional property of liposomes similar to that of cellular membranes, and can be applied to quantify the co-precipitated proteins by densitometric analyses [103,76]. PA-conjugated beads (e.g. agarose) are commercially available and have been successfully used in place of liposomes to discover novel PA-binding proteins [104,105]. In surface plasmon resonance (SPR) analysis, the protein of interest is chemically immobilized on the metal surface of a chip and its optical response is then monitored as a buffer containing PA flows through the chip surface. SPR enables real-time quantification of the bimolecular interaction for binding kinetic studies, such as determining the association/dissociation rates [21,25,26]. In addition to these in vitro techniques, PA–protein complex can be isolated from intact cells or tissues by immunoprecipitation and PA is then measured by mass spectrometry [21]. If the cells or tissues have been fed with fluorescently labeled PA, the presence of PA in the immunoprecipitated samples can be visualized by UV detection [21,23].

Effects of PA on protein localization

PA binding can alter biochemical properties of target proteins, such as catalytic activity, protein stability, and interaction with other molecules (Figure 2). Since most studies on PA–protein interaction have been performed under a non-cellular and/or physiological context, it is not fully understood how PA exerts such a variety of biochemical effects on its target proteins at the molecular level. One of direct consequences caused by PA is alteration of subcellular localization of proteins. Soluble proteins may be tethered to membranes where PA resides by being attracted to PA that acts like an ‘electromagnet’ switched on by extracellular stimuli. This is exemplified by PA-mediated association of Arabidopsisabscisic acid insensitive 1 (ABI1) with the plasma membrane [23] and yeast Opi1p with the ER [36]. Both ABI1 and Opi1p can move into nuclei and their regulatory activity is suppressed by being tethered to PA outside the nucleus. It should be noted that PA-mediated membrane association of proteins can sequester proteins from or bring them to their sites of action, and these interactions can represent an initial step for non-topological effects of PA as described below.

Structural effects on target proteins

Biochemical effects of PA on its target proteins have been proposed (through some structural studies) to be, in part, by inducing conformational changes in the proteins. For example, it has been reported that PA binding causes conformational changes in a transcriptional regulator peroxisome proliferator-activated receptor α (PPARα), leading to an increase in the α-helix content at the expense of the β-sheet content [106]. This results in a reduction in PPARα ability to bind the promoter of epidermal growth factor receptor (EGFR), and thereby represses the EGFR expression in cancer cells [106]. A similar secondary structural change promoted by PA has been observed in human cytochrome P450 1B1 (CYP1B1). PA increases thermal stability of CYP1B1, presumably through induction of more compact conformation by increasing the α-helix content, and thus enhances catalytic activity of the enzyme [107]. Enzyme activation by a PA-induced conformational change was also proposed for the serine/threonine kinase LKB1 [108]. Another study has shown that a membrane protein Sec18 undergoes PA-induced conformational changes that expose hydrophobic residues, making the protein susceptible to proteolytic attacks by trypsin and thrombin [77]. A similar mechanism may underlie the PA-induced proteolytic cleavage of glyceraldehyde-3-phosphate dehydrogenase (cytosolic; GAPC) that is observed in Arabidopsis, but not in E. coli or a cell-free system [26]. In addition, PA binding activates the guanine nucleotide exchange factor Son of sevenless (Sos) by allowing its histone domain (Sos-H) to adopt a conformation that destabilizes the autoinhibitory state of the enzyme [109]. PA also enhances a microtubule-associated protein MAP65-1 binding to microtubules, and thus promotes the polymerization and bundling of microtubules [110]. It has been proposed that the protein conformation possibly altered by PA binding is responsible for the enhanced binding of MAP65-1 [110]. Collectively, the PA-induced change in protein structure seems to be a conserved mechanism for PA action and the diversity of its outcomes, such as alterations of catalytic activity, protein stability, and interaction with other cellular components, is supported by no consensus PA-binding sequence present in PA target proteins.

Competitive effects on target proteins

In some PA-binding proteins, PA appears to share a binding site with their ligands or other effector molecules. PA directly binds to the mammalian target of rapamycin (mTOR) via the FKBP12-rapamycin-binding (FRB) domain that is targeted by rapamycin. Rapamycin has been shown to compete with PA for the same site, preventing mTOR from activating downstream effectors in human embryonic kidney 293 (HEK293) cells [111]. Similarly, it has been demonstrated that mTORcomplex 1 (mTORC1) kinase activity is stimulated by PA that competes with the mTORC1 inhibitor FK506 binding protein 38 (FKBP38) to disrupt mTORC1–FKBP38 interaction [112]. This study has also suggested that PA can allosterically stimulate mTORC1 activity, as well as by antagonizing the FKBP38 inhibition, from the observation that PA further stimulates mTORC1 in the absence of FKBP38 [112]. PA can not only regulate the microtubule polymerization for cytoskeletal organization, but has also been shown to promote assembly of actin filaments in Arabidopsis by binding the heterodimeric actin filament capping protein, Arabidopsis thalianacapping protein (AtCP) and preventing it from binding to the barbed ends of actin filaments [113,114]. Interestingly, a later structural computational study has predicted that PA binding to a C-terminal part of AtCP α subunit sterically hinders AtCP binding to actin filaments [115]. In addition, PA-induced disruption of protein–DNA interaction has been observed in vitro for some transcription factors, including late elongated hypocotyl (LHY) and an AT-hook motif-containing nuclear localized protein (AHL4) in Arabidopsis [21,39]. Although PA binding sites of LHY and AHL4 are not identified and possible PA-induced conformational change of the proteins cannot be ruled out, the PA inhibition of protein–DNA interaction suggests that PA may block DNA-binding site of the proteins, presumably by competitive binding of its phosphate group with that of DNA to specific basic residues in the proteins.

Effects on protein oligomerization

Protein oligomerization has been regarded as an initial mechanistic process common to antimicrobial peptides, but it is only recently that PA has been considered to play a key role in the process on microbial membranes. A recent study using X-ray crystallography has revealed that a plant cationic antimicrobial peptide defensin NsD7 (Nicotiana suaveolensdefensin 7) forms a double helical oligomeric complex in a manner dependent on PA interaction that occurs at the interface between NsD7 dimers [116]. This facilitates the permeabilization of PA-containing membranes of pathogens for the innate immune defense [116]. A similar PA-dependent oligomerization has been observed by another structural study using defensin NaD1 (Nicotiana alatadefensin 1), identifying a conserved membrane disruption mechanism for the defensin family across species [117]. Meanwhile, PA specifically interacts with four arginine residues in the N-terminus of a potassium channel KcsA, and thereby stabilizes its tetrameric structure on the cytosolic side of membranes [118]. Later, the stabilization of KcsA tetrameric structure by PA has turned out to be due to the α-helix and β-sheet contents increased by PA binding and possibly alteration of the protein folding [119]. PA also promotes both oligomerization and α-helix formation of a membrane protein α-synuclein implicated in Parkinson’s disease [82]. Taken together, PA is believed to help proteins to properly function on membranes in part by inducing their oligomerization and/or stabilizing preformed oligomeric structures.

Role of PA in membrane trafficking

The overall cone-shaped structure of PA (Figure 2, top) allows local accumulation of PA molecules to induce negative (concave) curvature in the lipid bilayer, which facilitates membrane fusion and fission and the formation of secretory vesicles [96,97]. Recently, disparate mechanisms for PA-induced membrane rearrangement have been proposed. PA can induce spontaneous negative curvature of membranes, bind and regulate proteins/enzymes required for vesicle fission/fusion, and be converted into other lipids, such as DAG and LPA, important to membrane remodeling [10,11]. This mechanistic diversity accounts for the multiple, even opposite effects of PA frequently observed on vesicle fusion/fission. The presence of PA in the outer leaflet of a membrane should inhibit membrane fission, but in some cases rather promotes it, for example on trans-Golgi network by recruiting a fission-inducing protein C-terminal-binding protein1-S/brefeldin A ADP-ribosylation substrate (CtBP1-S/BARS) [120,121]. Likewise, PA is able to both promote and inhibit soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE)-mediated membrane fusion by interacting with different sets of SNARE proteins [58,76,122–124]. PA can also promote mitochondrial fusion by stimulating mitofusin 1-mediated fusion and suppressing fission-inducing dynamin-related protein 1 (Drp1) [66,125,126].

A unique role of PA in the completion of vesicle fusion process has been revealed by a yeast vacuole fusion assay demonstrating that PA cannot be replaced by other cone-shaped lipids (e.g. DAG) [56]. In plants, PA binds to and activates ARF GTPase-activating protein domain 7 (AGD7), an ADP-ribosylation factor (ARF) GTPase-activating protein homolog in Arabidopsis, thus inactivates ARF for the regulation of vesicle formation [127,128]. Finally, PA is known to play a key role in determining the size of lipid droplets, storage lipid-packed organelles covered by a phospholipid monolayer, as well as in their budding from the ER by reducing surface tension of ER membrane [129–131]. Those observations suggest a complex mode of PA actions; it is conceivable that a combination of the mechanisms mentioned above, possibly with yet unidentified effects of PA, underlies a given event of membrane trafficking.

Conclusion and perspectives

PA is a minor class of lipids present in cell membranes and a central intermediate for the synthesis of membrane and storage lipids. Moreover, its unique structural and chemical properties, ubiquitous and dynamic nature of occurrence, and pleiotropic effects on proteins allow the small lipid to be a versatile mediator involved in numerous cellular and physiological processes in living organisms. Its signaling and metabolic roles in both animal and plant kingdoms may present PA as an attractive cellular target for human therapeutics and enhancement of crop performance. PA and its metabolizing enzymes, such as PLDs, have been implicated in a variety of pathologies associated with PA levels and PLD activities dysregulated, including neurodegenerative diseases, blood disorders, and cancers, leading to therapeutic attempts to develop potent and specific inhibitors of PLD [10,74,132]. Likewise, genes encoding enzymes involved in PA metabolism have been manipulated to explore their potential application for crop improvement, based on intriguing observations of PA effects on plant growth, development, and stress responses [133,134]. Therefore, further investigations of the multifaceted PA functions have the potential for not only a better understanding of cell signaling mechanisms, but also novel ideas for practical applications.

Summary

  • PA is widely found in cell membranes of all biological kingdoms and its content and composition undergo rapid changes in response to stimulation in plants.

  • PA is a key intermediate for lipid metabolism and a signaling messenger involved in various metabolic, cellular, and physiological processes.

  • PA interacts with proteins and alters their conformation, oligomerization, subcellular association, and/or molecular interaction.

  • Further studies are needed to understand the mechanism of PA action and its multifaceted metabolic and regulatory effects.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Agriculture and Food Research Initiative (AFRI) [grant number 2016-67013-24429 (to X.W.)]; the USDA National Institute of Food and Agriculture [project accession number 1007600]; the National Science Foundation [grant number MCB-1412901]; and the U.S. Department of Energy [grant number DE-SC0001295]. The Lipidomic instrumentation is supported by the National Science Foundation [grant number DBI-1427621].

Author Contribution

S.-C.K. wrote the article and X.W. commented and revised the article.

Abbreviations

     
  • ABI1

    abscisic acid insensitive 1

  •  
  • AHL4

    AT-hook motif-containing nuclear localized protein 4

  •  
  • ARF

    ADP-ribosylation factor

  •  
  • AtCP

    Arabidopsis thaliana capping protein

  •  
  • CDP

    cytidyldiphosphate

  •  
  • CYP1B1

    cytochrome P450 1B1

  •  
  • DAG

    diacylglycerol

  •  
  • DGK

    DAG kinase

  •  
  • DGPP

    DAG pyrophosphate

  •  
  • DHAP

    dihydroxyacetone phosphate

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • ER

    endoplasmic reticulum

  •  
  • FKBP38

    FK506 binding protein 38

  •  
  • G3P

    glycerol 3-phosphate

  •  
  • LHY

    late elongated hypocotyl

  •  
  • LPA

    lysophosphatidic acid

  •  
  • LPP

    lipid phosphate phosphatase

  •  
  • MAP65-1

    microtubule-associated protein 65-1

  •  
  • MCS

    membrane contact site

  •  
  • MIM

    mitochondrial inner membrane

  •  
  • MOM

    mitochondrial outer membrane

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • mTORC1

    mTOR complex 1

  •  
  • NPC

    nonspecific PLC

  •  
  • Nsd7

    Nicotiana suaveolens defensin 7

  •  
  • Opi1p

    overproduction of inositol 1 protein

  •  
  • PA/PtdOH

    phosphatidic acid

  •  
  • PAP

    PA phosphatase

  •  
  • PC/PtdCho

    phosphatidylcholine

  •  
  • PE/PtdEtn

    phosphatidylethanolamine

  •  
  • PLD

    phospholipase D

  •  
  • PPARα

    peroxisome proliferator-activated receptor α

  •  
  • sn

    stereospecific numbering

  •  
  • SNARE

    soluble N-ethylmaleimide-sensitive-factor attachment protein receptor

  •  
  • Sos

    Son of sevenless

  •  
  • SPR

    surface plasmon resonance

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