Phospholipase A2 (PLA2) hydrolyzes the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. In the view of signal transduction, the PLA2 reaction has been considered to be of particular importance since arachidonic acid, one of the polyunsaturated fatty acids released by PLA2, is metabolized by cyclooxygenases and lipoxygenases to the potent lipid mediators prostaglandins and leukotrienes, which are often referred to as eicosanoids. In addition, lysophospholipids or their metabolites, such as lysophosphatidic acid (LPA) and platelet-activating factor (PAF), represent another class of lipid mediators. These lipid mediators exert numerous biological actions through their cognate G protein-coupled receptors on target cells. PLA2 has also been implicated in membrane glycerophospholipid remodeling, thereby contributing to cellular homeostasis.
The PLA2 enzymatic activity was originally identified more than a century ago in snake venom that potently hydrolyzed egg phosphatidylcholine (PC). By the 1980s, many secreted PLA2s (sPLA2s) were purified from various venomous animal species including snakes and insects as well as from pancreatic juices in various animals. Pancreatic sPLA2, the first sPLA2 subtype identified in mammals, is now called group IB sPLA2. In the late 1980s, several groups purified and cloned the second mammalian sPLA2 that was markedly induced in inflammatory fluids of human and various animal species. This second type of sPLA2, now called group IIA sPLA2 (also known as an inflammatory sPLA2), was thus supposed to play a key role in the production of arachidonic acid-derived lipid mediators in various inflammatory diseases. In the early 1990s, however, the situation became more complex with the identification of the first intracellular PLA2, i.e., cytosolic PLA2 group IVA (cPLA2α). Because of its specificity for phospholipids with arachidonic acid and its unique properties to undergo stimulus-coupled membrane translocation and phosphorylation, much of the interest was shifted to this enzyme as a central regulator of arachidonic acid metabolism. Meanwhile, the late 1990s saw a rapid increase in the discovery of multiple sPLA2s as well as many other intracellular PLA2s including Ca2+-independent PLA2s (iPLA2s), PAF acetylhydrolases, lysosomal PLA2s, and so on, by means of in silico database searches followed by molecular cloning. So far, it is now known that human and mouse genomes encode genes for more than 30 PLA2s or related enzymes, among which the cPLA2 (6 isoforms), iPLA2 (9 isoforms), and sPLA2 (11 isoforms) families represent three major groups.
cPLA2α-deficient mice, which were first reported in 1997 (Uozumi et al. 1997; Bonventre et al. 1997), have provided unequivocal evidence for the central role of this enzyme in arachidonic acid metabolism in many, if not all, biological events. Since the beginning of the twenty-first century, mice with transgenic overexpression and/or targeted disruption of many PLA2 subtypes have been generated. The phenotypes displayed in individual PLA2 gene-manipulated mice might not be simply the reflection of changes in lipid mediator signaling or more particularly eicosanoid signaling, but could be due to the hydrolysis of one or a combination of various target membranes. In addition, mutations of several PLA2s are linked with human diseases. Here, the properties and functions of PLA2s in the three major groups (cPLA2, iPLA2, and sPLA2) are overviewed.
Cytosolic PLA2s (cPLA2s)
The overall topology of the C2 domain, which is essential for membrane translocation of cPLA2α in response to calcium signaling, consists of eight antiparallel β-strands interconnected by six loops. Two Ca2+ ions bind at one end of the C2 domain. The membrane binding of cPLA2α is driven by hydrophobic interactions that are achieved by the penetration of hydrophobic residues in the C2 domain into the PC-rich membrane core. The catalytic domain of cPLA2α is composed of 14 β-strands and 13 α-helices. During the nucleophilic Ser228 attacks at the sn-2 ester bond of glycerophospholipids, Asp549 contributes to the activation of this catalytic center. Within the active-site channel, which penetrates one third of the way into the catalytic domain, the catalytic dyad (Ser228 and Asp549) is placed at the bottom of a deep and narrow cleft. The funnel is lined with hydrophobic residues and forms a cradle, to which fatty acyl moieties of phospholipids may bind. Ser505, which represents a phosphorylation site by MAP kinases, is located near the interdomain linker region (Dessen et al. 1999).
The C2 domain-directed, Ca2+-dependent translocation of cPLA2α from the cytosol to the Golgi and perinuclear membranes is essential for the initiation of arachidonic acid release and subsequent eicosanoid production in agonist-stimulated cells (Clark et al. 1991). In addition to the C2 domain, the catalytic domain contributes to membrane residence of cPLA2α. Beyond the regulatory role of calcium signaling, the maximal activation of cPLA2α in cells requires sustained phosphorylation of Ser505 by MAP kinases (Lin et al. 1993). The main role of Ser505 phosphorylation is to promote membrane penetration of hydrophobic residues in the active-site rim by inducing a conformational change of the protein, and these enhanced hydrophobic interactions allow the sustained membrane interaction of cPLA2α in response to transient Ca2+ increase at a submicromolar level. The full activation of cPLA2α is achieved by additional phosphorylation at Ser727 by MAP kinase-activated protein kinases that disrupts the inhibitory interaction of annexin A2 with cPLA2α. Phosphatidylinositol 4,5-bisphosphate (PIP2) binds with high affinity and specificity to cPLA2α. Mutations in PIP2 binding sites (Lys488/Lys543/Lys544) reduce arachidonic acid release from cells without alteration in Ca2+-dependent translocation or interfacial binding to membranes, indicating that PIP2 binding in the catalytic domain principally acts to regulate cPLA2α hydrolytic activity (Tucker et al. 2009). In addition, ceramide-1-phosphate (C1P) interacts directly with the cationic β-groove of the C2 domain and may contribute to translocation of cPLA2α to Golgi membranes in response to stimuli.
cPLA2α-deficient mice display a number of phenotypes, most of which can be explained by the reduction of lipid mediators including eicosanoids and PAF (Uozumi et al. 1997; Bonventre et al. 1997; Nagase et al. 2000). Production of these lipid mediators is markedly if not solely reduced in inflammatory cells such as macrophages, neutrophils, and mast cells in cPLA2α-deficient mice. The null mice are protected from airway disease models such as asthma, acute respiratory distress syndrome, and pulmonary fibrosis; brain injury models such as ischemia and amyloid β-induced deficits in learning and memory; autoimmune disease models such as experimental autoimmune encephalomyelitis and collagen-induced arthritis; intestinal cancer; and atherosclerosis, among others. Beyond these roles in pathology, the cPLA2α-dependent eicosanoid pathway is also important for tissue homeostasis, as ablation of cPLA2α perturbs female reproduction, renal function, platelet function, gastrointestinal barrier, and long-term depression in cerebellar Purkinje cells.
Ca2+-Independent PLA2s (iPLA2s)
iPLA2β (PNPLA9 or PLA2G6) is a prototypic iPLA2 enzyme that is ubiquitously expressed in various cells and occurs as several splice variants. iPLA2β shows no strict specificity with respect to sn-2 fatty acid and head group of the substrate phospholipids, is fully active in the absence of Ca2+, and also exhibits sn-1 lysophospholipase activity and transacylase activity. Like other PNPLA enzymes, iPLA2β has a conserved nucleotide-binding motif proximal to the catalytic site. The N-terminal domain of iPLA2β has eight to nine ankyrin repeats, which contribute to a tetramer formation and give a negative effect on the enzymatic catalysis. Because of its Ca2+-independent property, iPLA2β has long been thought to be involved in homeostatic phospholipid remodeling through deacylation of phospholipids in the Land’s cycle. However, accumulating evidence suggests that iPLA2β plays more diverse roles in cellular signaling leading to cell activation, proliferation, migration, or apoptosis. Genetic screening of Drosophila points Orai1 and STIM1 (components of store-operated Ca2+ entry (SOCE) channels) as well as an ortholog of iPLA2β (CG6718) as gene products giving a great impact on SOCE (Vig et al. 2006). iPLA2β has a binding site for calmodulin near the C-terminus, and the association with calmodulin leads to inactivation of iPLA2β. Activation of SOCE channels and capacitative Ca2+ influx, which are triggered by depletion of intracellular Ca2+ stores, displaces inhibitory calmodulin from iPLA2β, resulting in activation of iPLA2β and generation of lysophospholipids that ultimately activate capacitative Ca2+ influx (Bolotina 2008). Given this theory, the SOCE-mediated activation of iPLA2β lies upstream of Ca2+-dependent activation of cPLA2α. In apoptotic cells, iPLA2β is cleaved at one or multiple sites by caspase-3, an event that enhances the catalytic activity of iPLA2β. Inhibition of iPLA2β suppresses phosphatidylserine externalization at an early phase of apoptosis, suggesting that the caspase-truncated form of iPLA2β accelerates apoptotic membranous changes. Strikingly, lysophosphatidylcholine (LPC) produced by the caspase-3-cleaved iPLA2β is released from apoptotic cells and acts as an attracting (“find-me”) signal for phagocytes (Lauber et al. 2003). Thus, during the process of inflammation, in which extravasation of neutrophils to the site of inflammation precedes a second wave of emigrating monocytes, the emigrated neutrophils undergo apoptosis leading to iPLA2β-promoted generation of LPC, which in turn attracts monocytes.
Analyses of iPLA2β-deficient and -transgenic mice have revealed broad roles of this enzyme in stimulus-induced arachidonic acid release, sperm motility, vascular contractility and relaxation, apoptosis induced by endoplasmic reticulum stress, antiviral response, age-related bone loss, glucose-stimulated insulin secretion by pancreatic β-cells, tumorigenesis, and neurodegeneration, among others (Bao et al. 2006; Shinzawa et al. 2008). Because of impaired islet secretory reserve, a high-fat diet induces severe glucose intolerance in iPLA2β-null mice, whereas the glucose tolerance is improved in β-cell-specific iPLA2β-transgenic mice (Bao et al. 2006). Tumorigenesis and ascites formation are ameliorated in iPLA2β-null mice, and the iPLA2β gene haplotypes in humans are strongly associated with a higher risk of colorectal cancer (Hoeft et al. 2010). A locus for the neuroaxonal dystrophies such as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and parkinsonism, which harbor the distinctive pathologic feature of axonal degeneration with distended axons (spheroid bodies) throughout the central nervous system, is mapped to the human iPLA2β gene (Morgan et al. 2006). Likewise, mice with iPLA2β deficiency or point mutation display severe motor dysfunction due to widespread degeneration of axons and synapses, accompanied by formation of numerous spheroids and vacuoles (Shinzawa et al. 2008). Distinct mutations in iPLA2β gene (also called PARK14) are associated with familial Parkinsonism, and genetic or molecular impairment of iPLA2β-dependent Ca2+ signaling (see above) triggers autophagic dysfunction, progressive loss of dopaminergic neurons, and age-dependent motor dysfunction (Zhou et al. 2016).
iPLA2γ (PNPLA8) has four potential translation initiation sites, which produce distinct sizes of the protein. iPLA2γ catalyzes the cleavage of fatty acids from the sn-1 or sn-2 position of phospholipids depending upon the substrates. Remarkably, iPLA2γ has a mitochondrial and a peroxisomal localization signal in the N- and C-terminal regions, respectively, and are preferentially distributed in these organelles. Mice null for iPLA2γ display multiple bioenergetic dysfunctional phenotypes, including growth retardation, cold intolerance, reduced exercise endurance, increased mortality from cardiac stress after transverse aortic constriction, skeletal muscle atrophy, abnormal mitochondrial function with a dramatic decrease in oxygen consumption, and hippocampal neurodegeneration with massive autophagy and cognitive dysfunction (Mancuso et al. 2009). iPLA2γ-deficient mice are also resistant to diet-induced obesity, hyperlipidemia, and insulin intolerance (Song et al. 2010). Importantly, the reduction in tissue cardiolipin content, accompanied by an altered cardiolipin molecular composition, in iPLA2γ-deficient mice indicates that this iPLA2 isoform may be involved in mitochondrial cardiolipin remodeling. The phenotypes of iPLA2γ-deficient mice are reminiscent of Barth syndrome, an X-linked cardioskeletal myopathy accompanied by exercise intolerance and neutropenia, which is caused by mutations in the gene encoding tafazzin, a mitochondrial phospholipid-lysophospholipid transacylase. Loss-of function variants of human iPLA2γ recapitulate the mitochondriopathy observed in iPLA2γ-null mice (Saunders et al. 2015).
Secreted PLA2s (sPLA2s)
Group IB sPLA2 has a unique five amino acid extension termed the pancreatic loop in the middle part of the molecule and a group I-specific disulfide between Cys11 and Cys77. It is synthesized in the pancreatic acinar cells, and after secretion into the pancreatic juice, an N-terminal heptapeptide of the inactive zymogen is cleaved by trypsin to yield an active enzyme in the duodenum. The main role of this pancreatic sPLA2 is digestion of dietary and biliary phospholipids in the small intestine. Perturbation of this process by gene disruption or pharmacological inhibition of group IB sPLA2 leads to protection from diet-induced obesity and insulin resistance due to decreased lipid digestion and absorption in the gut (Labonté et al. 2010).
Group IIA sPLA2 has a group II-specific disulfide linking Cys50 to the C-terminal Cys and a C-terminal extension of seven amino acids in length. The levels of group IIA sPLA2 in sera or exudative fluids are well correlated with the severity of inflammatory disease: this is the reason why this isozyme is often called inflammatory sPLA2. The best-recognized physiologic function of group IIA sPLA2 is the degradation of bacterial membranes, thereby providing the first line of antimicrobial defense of the host (Pernet et al. 2014; Weinrauch et al. 1998). When overexpressed in cultured cells, group IIA sPLA2 is capable of augmenting arachidonic acid release after cytokine stimulation. However, the contribution of group IIA sPLA2 to inflammation has remained a subject to debate until recently, since a natural frameshift mutation of its gene in C57BL/6 and 129 Sv mice prevents the proper assessment of its functions by a classical gene targeting strategy. A recent study using group IIA sPLA2-deficient BALB/c mice has provided evidence that the enzyme does play an exacerbating role in arthritis (Boilard et al. 2010). Mechanistically, group IIA sPLA2 hydrolyzes phospholipids in microparticles, particularly in extracellular mitochondria (an organelle that evolutionally originated from bacteria), which are released from activated platelets or leukocytes at inflamed sites (Boudreau et al. 2014). Hydrolytic breakdown of microparticular membranes by group IIA sPLA2 gives rise to inflammatory mediators including eicosanoids and lysophospholipids as well as mitochondrial DNA as a danger-associated molecular pattern (DAMP), leading to augmented inflammation. Hence, group IIA sPLA2 is primarily involved in host defense by killing bacteria and triggering innate immunity, whereas over-amplification of the response leads to exacerbation of inflammation. Group IIA sPLA2 is abundantly expressed in intestinal Paneth cells, and mouse strains with a natural frameshit mutation in its gene are more sensitive to colon cancer (MacPhee et al. 1995). As a potential mechanism, group IIA sPLA2 modulates intestinal stem cell function and Paneth cell differentiation through regulation of Wnt signaling, and therefore its absence increases colon cancer susceptibility (Schewe et al. 2016). The serum level of group IIA sPLA2 also shows good correlation with the risk of cardiovascular diseases, and group IIA sPLA2-transgenic mice develop atherosclerosis when fed an atherogenic diet. This effect may be due to sPLA2-mediated hydrolysis of low-density lipoprotein (LDL) phospholipids leading to generation of small-dense, proatherogenic LDL particles that facilitate macrophage foam cell formation. However, the role of group IIA (and any other classical) sPLA2s in atherosclerosis is enigmatic, since a phase III clinical trial for atherosclerosis using a classical sPLA2 inhibitor (valespladib) failed to show efficacy (Nicholls et al. 2014).
Group IIC sPLA2 has an additional disulfide bond between Cys87 and Cys93 in an extended loop region and is expressed in rodent testis. In the human genome, however, it is encoded by a pseudogene and not expressed as a functional protein.
Group IID sPLA2 is structurally most similar to group IIA sPLA2 and is constitutively expressed in dendritic cells (DCs) in lymphoid organs. Group IID sPLA2 attenuates DC-mediated adoptive immune responses by releasing antiinflammatory ω3 polyunsaturated fatty acids (e.g., docosahexaenoic acid; DHA) and their metabolites (e.g., resolvins) (Miki et al. 2013). As such, group IID sPLA2-deficient mice exhibit more severe contact hypersensitivity and psoriasis, whereas they are protected against infection and cancer because of enhanced antiviral and antitumor immunity (Miki et al. 2016; Vijay et al. 2015). In line with its immunosuppressive role, expression of this enzyme in DCs is downregulated following inflammation.
Group IIE sPLA2, which is another group IIA-related enzyme, is expressed in hair follicles in association with hair cycling and induced in adipose tissue in association with obesity in mice. It preferentially hydrolyzes phosphatidylethanolamine in hair follicles and lipoproteins. Group IIE sPLA2-deficient mice display subtle abnormalities in hair follicles (Yamamoto et al. 2016) and are modestly protected from diet-induced obesity and hyperlipidemia (Sato et al. 2014). However, expression of this enzyme in human is unclear.
Group IIF sPLA2 possesses a unique 30-amino acid C-terminal extension that contains an additional cysteine residue, which might contribute to the formation of a homodimer or a heterodimer with a second protein. Group IIF sPLA2 is expressed most abundantly in the skin and is induced by IL-22, a Th17 cytokine, in differentiating keratinocytes. This enzyme facilitates epidermal hyperplasia by producing plasmalogen lysophosphatidylethanolamine. Group IIF sPLA2-null mice are protected from epidermal hyperplasia in the context of psoriasis and skin cancer, whereas its transgenic mice spontaneously develop psoriasis-like skin abnormalities (Yamamoto et al. 2015).
Group V sPLA2 does not possess the group I- and group II-specific disulfides and the group II-specific C-terminal extension. Gene ablation of group V sPLA2 in mice results in partial reduction of eicosanoid production in zymosan-stimulated macrophages (Satake et al. 2004). Group V sPLA2-null mice are protected from fungal infection, since macrophages in the null mice show reduced phagocytosis of fungal particles (Balestrieri et al. 2009). Contrary to mice lacking group IIA sPLA2 (see above), those lacking group V sPLA2 are more sensitive to inflammatory arthritis, likely because macrophage phagocytosis of the immune complex, a process that depends on cysteinyl leukotrienes, is reduced in the arthritic joints (Boilard et al. 2010). LDL receptor-deficient mice transplanted with group V sPLA2-null bone marrow cells are modestly protected from atherosclerosis development, yet its global deficiency does not profoundly affect the disease. Group V sPLA2 is induced in adipocytes during diet-induced obesity and hydrolyzes PC in hyperlipidemic LDL to preferentially release oleate, which in turn counteracts palmitate-induced adipose tissue inflammation and thereby ameliorates metabolic disorders (Sato et al. 2014). Consistently, a single nucleotide polymorphism of the human group V sPLA2 gene haplotype is associated with LDL levels in patients with type 2 diabetes. Group V sPLA2 is induced in bronchial epithelial cells and M2 macrophages by the Th2 cytokines IL-4 and IL-13, and its gene ablation in mice leads to reduced Th2 immunity and protection from airway disorders such as asthma and respiratory distress syndrome (Ohta et al. 2013). Pulmonary surfactant, a lipid-protein complex that lowers surface tension along the alveolar epithelium and thereby promotes alveolar stability, is a good substrate for group V sPLA2. Accordingly, transgenic overexpression of this enzyme in mice causes aberrant hydrolysis of surfactant PC, leading to neonatal death (Ohtsuki et al. 2006). In the kidney, group V sPLA2 is involved in urinary tubular integrity and sodium handling (Silva-Filho et al. 2016).
Group X sPLA2 has both the group I- and II-specific disulfides, the group II-specific C-terminal extension, and the group I-specific propeptide. Like group IB sPLA2, group X sPLA2 is synthesized as a zymogen, and the removal of the N-terminal propeptide produces an active mature enzyme. Among the mammalian sPLA2s, group X sPLA2 shows the highest binding affinity for PC and thus exhibits the most potent activity to release arachidonic acid and LPC from target cell membranes. Group X sPLA2 is mainly expressed in the gastrointestinal epithelium, testis, and to a lesser extent airway epithelial cells. Group X sPLA2-null mice are refractory to antigen-induced asthma, with markedly reduced eosinophil and lymphocyte infiltration and reduced cytokine and eicosanoid levels (Henderson et al. 2007). The null mice are also protected from neutrophil-induced myocardial damage following ischemia-reperfusion (Fujioka et al. 2008). Group X sPLA2 is released from sperm acrosomes, and its absence perturbs acrosome reaction and fertility of spermatozoa in mice (Escoffier et al. 2010). Although group X sPLA2 is potently active on LDL phospholipids in vitro, its role in atherosclerosis in vivo remains controversial. In the gut, group X sPLA2 protects against colitis by releasing antiinflammatory ω3 polyunsaturated fatty acids (Murase et al. 2016) and against colon cancer by acting on sPLA2 receptor (Schewe et al. 2016).
Group III sPLA2 is an unusually large protein (55 kDa) among the sPLA2 family and consists of three domains, in which the central sPLA2 domain that displays all of the features of bee venom sPLA2, including 10 cysteines and the key residues of the Ca2+ loop and catalytic site, is flanked by large and unique N- and C-terminal regions. The enzyme is processed to the sPLA2 domain-only form that retains full enzymatic activity. Transgenic overexpression of group III sPLA2 in mice results in increased atherosclerosis due to accelerated LDL hydrolysis and in increased inflammation due to elevated eicosanoid formation (Sato et al. 2008). Knockout of group III sPLA2 in mice has revealed unexplored roles of this atypical sPLA2 in epididymal sperm maturation through regulating sperm membrane remodeling (Sato et al. 2010) and in mast cell maturation and thereby anaphylaxis through driving a paracrine prostaglandin D2 circuit (Taketomi et al. 2013).
Group XIIA sPLA2 is a 19-kDa enzyme containing a central catalytic domain with a His-Asp catalytic dyad, yet the locations of cysteines outside the catalytic domain are far distinct from those of other sPLA2s. High expression of this enzyme is found in many tissues, yet its enzymatic activity is rather weaker than that of other sPLA2s. A study using gain-of-function of group XIIA sPLA2 in Xenopus embryos suggests the role of this enzyme in early neuronal development, particularly olfactory sensory structures (MulfacSanjuct and Brivanlou. 2005).
Group XIIB sPLA2 is catalytically inactive since the catalytic center His is replaced with Leu. Its deficiency perturbs hepatic VLDL secretion (Guan et al. 2011), although the underlying mechanism is entirely unclear.
The understanding of the biological functions of all PLA2s is now a challenging area of research and will be clarified hopefully in the next decade. The control of particular PLA2 activities should have advantages over the inhibition of selective lipid mediator pathways and of some other biological events in the treatment of pathological states. Since more than one PLA2 are likely to be involved in the pathology of various diseases in either a positive or negative way, the understanding of the expression, function, and regulation of each PLA2 in specific tissues and disease states would be of particular importance. In certain situations, it would be favorable to control the activity of a particular PLA2 subtype for the treatment of particular disorders.
This work was supported by AMED-CREST and JSPS KAKENHI (16H02613 and 15H05905).
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