Diversity and regulatory functions of mammalian secretory phospholipase A2s

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ADVANCES IN IMMUNOLOGY, VOL. 77

Diversity and Regulatory Functions of Mammalian Secretory Phospholipase A2s MAKOTO MURAKAMI AND ICHIRO KUDO Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

I. Introduction

Phospholipase A2 (PLA2) has emerged as a growing superfamily of enzymes that catalyze the hydrolysis of membrane glycerophospholipids at the sn-2 position, liberating free fatty acids and lysophospholipids. PLA2 provides precursors for the biosynthesis of eicosanoids, such as prostaglandins (PGs) and leukotrienes, when the liberated fatty acid is arachidonic acid (AA), as well as lysophospholipid-derived mediators, such as platelet-activating factor (PAF) and lysophosphatidic acid. As overproduction of these lipid mediators causes various diseases and tissue disorders, it is important to understand the mechanisms that regulate the functions of PLA2. Recent advances in molecular and cellular biology have led to the identification of a number of mammalian PLA2 enzymes, which are subdivided into several groups based on their structures, enzymatic characteristics, subcellular distributions, and cellular functions. There are four major families of PLA2: secretory PLA2s (sPLA2s), cytosolic PLA2s (cPLA2s), Ca2+ -independent PLA2s (iPLA2s), and PAF acetylhydrolases (PAF-AH). Among them, cPLA2 (group IV) has received much attention as a key regulator of stimulus-initiated eicosanoid and PAF biosynthesis, because it selectively releases AA, shows submicromolar Ca2+ sensitivity, and is activated by mitogen-activated protein kinase–directed phosphorylation (Clark et al., 1991; Lin et al., 1993). cPLA2 undergoes Ca2+-dependent translocation from the cytosol to perinuclear and endoplasmic reticular membranes, where several downstream eicosanoid-generating enzymes, including cyclooxygenase (COX) and lipoxygenase (LOX), are localized (Schievella et al., 1995). Studies of cPLA2-deficient mice have confirmed its critical role in lipid mediator generation during the acute allergic response, parturition, and postischemic brain injury (Bonventre et al., 1997; Uozumi et al., 1997). Cytosolic iPLA2 (group VI), which occurs as several splicing variants (Larsson et al., 1998; Tang et al., 1997), plays a pivotal role in the phospholipid remodeling reaction (Balsinde et al., 1997). PAF-AHs (groups VII and VIII) are a group of unique PLA2 subtypes that degrade PAF and related oxidized phospholipids, thereby contributing to sequestering inflammatory responses (Hattori et al., 1994, 1996; Nakajima et al., 1997; Stafforini et al., 1997). 163 C 2001 by Academic Press Copyright  All rights of reproduction in any form reserved. 0065-2776/01 $35.00

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sPLA2 comprises Ca2+-dependent interfacial enzymes that share a low molecular mass (∼14–16 kDa). Numerous sPLA2s have been found in venom from vertebrate and invertebrate animals as well as in plants. To date, at least ten structurally related isozymes (groups IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XII) have been identified in mammals: these enzymes display distinct yet partially overlapping tissue distributions (Cupillard et al., 1997; Gelb et al., 2000; Ishizaki et al., 1999; Kramer et al., 1989; Seilhamer et al., 1989a; Suzuki et al., 2000, Tischfield, 1997; Valentin et al., 1999a,b, 2000). Continued awareness of the diversity of sPLA2s has cast doubt on earlier studies reporting the molecular identity of sPLA2 species expressed in various cells. Understanding the physiological functions of various sPLA2s is now a complex and challenging area of research in the eicosanoid field. Although the biological roles of each of these enzymes has not yet been clearly defined, they have been implicated in various physiological and pathological functions, including lipid digestion, lipid mediator generation, cell proliferation, exocytosis, antibacterial defense, cancer, and inflammatory diseases. In this chapter, we introduce the recent advances in the diversity, enzymatic properties, and functions of the sPLA2 family. In particular, the roles of each sPLA2 in eicosanoid generation in the context of functional coupling between other eicosanoid-biosynthetic enzymes in different phases of cell activation are described. II. Structures and Enzymatic Properties of sPLA2s

A. STRUCTURES The structural features of mammalian sPLA2s are summarized in Fig. 1 sPLA2s (except sPLA2-III; see below) contain highly conserved amino acid residues and sequences that are characteristic of most sPLA2s sequenced to date: (i) an -helical N-terminal segment containing lipophilic residues at positions 2, 5, and 9; (ii) a Ca2+-binding loop with a typical glycine-rich sequence at Tyr25–Pro37 and at the residue Asp49; (iii) an active site residue His48 as well as residues Tyr52, Tyr73 and Asp99; and (iv) 12–16 cysteine residues, most of which are in the same positions. sPLA2-IB (and snake venom group I sPLA2s) possesses 14 cysteines, of which residues 11 and 77 form a characteristic disulfide bond, an N-terminal propeptide, which is removed during the secretion/activation process, and an extra segment called the pancreatic loop (residues 54–56) (Murakami et al., 1997; Verheij et al., 1981). The gene for sPLA2-IB has been mapped to human chromosome 12 and mouse chromosome 5 (Seilhamer et al., 1989b). The group II subfamily of sPLA2s includes six isozymes (IIA, IIC, IID, IIE, IIF, and V), which possess similar structural characteristics that are not found in sPLA2-IB, and their genes are tightly clustered in the same chromosomal locus (human chromosome 1 and mouse chromosome 4) (Tischfield, 1997; Valentin et al., 1999a,b).

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FIG. 1. The structures of mammalian secretory phospholipase A2s (sPLA2s). The genes for sPLA2-IIA, -IIC, -IID, -IIE, -IIF, and -V (the group II subfamily of sPLA2s) map to the same chromosomal locus.

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FIG. 2. The phylogenetic tree of mammalian secretory phospholipase A2s.

sPLA2s-IIA, -IID, and -IIE display all of the specific features of group II sPLA2s (including snake venom group II enzymes), possessing a cysteine at position 50 and a cysteine that terminates the group II–specific C-terminal extension composed of seven residues (Ishizaki et al., 1999; Kramer et al., 1989; Seilhamer et al., 1989a; Suzuki et al., 2000; Valentin et al., 1999a,b). The refined threedimensional crystal structure of human sPLA2-IIA indicates that its catalytic mechanism is essentially identical to those inferred from the crystal structures of other venom and pancreatic group I and venom II sPLA2s (Scott et al., 1991; Wery et al., 1991). sPLA2-IIC is unique in that it has 16 cysteines, of which residues Cys86 and Cys92 are postulated to form an extra disulfide bridge (Chen et al., 1994b). This isozyme is expressed as an active enzyme in rodents, but is present in the form of a pseudogene in humans. sPLA2-IIF has a long C-terminal extension of 23 amino acids containing an extra cysteine (Valentin et al., 1999b). sPLA2-V has only 12 cysteines and lacks a group II–specific Cys50 and C-terminal extension (Chen et al., 1994a), yet its overall properties, revealed by the phylogenetic tree (Fig. 2), are more similar to those of the other group II subfamily of sPLA2s than to those of sPLA2-IB and -X. sPLA2-X, which has 16 cysteines, exhibits several structural features that are found in both groups I and II, including a group I–specific N-terminal propeptide, group I– and group II–specific disulfide bridges, and a group II– specific C-terminal extension (Cupillard et al., 1997). sPLA2-X is the only isozyme that undergoes N-glycosylation, although this sugar chain is not essential for catalytic function (Hanasaki et al., 1999). The gene for human sPLA2-X has been mapped to chromosome 16 (Cupillard et al., 1997). The amino acid sequence homology among these sPLA2s of the same species is ∼30–50%, and the

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exon–intron structures of their genes resemble one another, indicating that they are evolutionarily conserved. Besides these sPLA2s, onconin 90, a major protein component of otoconia, contains two domains homologous to sPLA2 (Wang et al., 1998). Alignment of the sPLA2-like domains in onconin 90 with the known sPLA2s reveals a highly conserved region close to the N terminus, which includes the Ca2+-binding loop and catalytic site. However, some of the residues considered essential for Ca2+binding and catalytic activity are replaced in both the sPLA2-like domains, suggesting that onconin 90 has no enzymatic function. The phylogenetic tree places the sPLA2-like domains in onconin 90, sPLA2-IB and sPLA2-X, on the same branch ancestral to other contemporarily expressed mammalian sPLA2s (Fig. 2). Very recently, another novel class of sPLA2, group XII, has been identified (Gelb et al., 2000). This isozyme displays homology to other sPLA2s only over a short stretch of amino acids in the active site region. The activity is Ca2+dependent (albeit weak) despite the fact that it has an unusual Ca2+-binding loop. B. ENZYMATIC PROPERTIES Mechanistic studies have shown that the sPLA2s do not form a classical acyl enzyme intermediate characteristic of serine esterases, including cPLA2s, iPLA2s, and PAF-AHs. Instead, they utilize the catalytic site His48, assisted by Asp49, to polarize a bound water, which then attacks the carbonyl group: the essential Ca2+ ion, bound in the conserved Ca2+-binding loop, stabilizes the transition state (Dennis, 1994). In vitro PLA2 assays provide somewhat varied results according to the protocol used. Generally, sPLA2s do not discriminate between fatty acid moieties at the sn-2 position, but have rather more specificity for the polarized head groups (Kudo et al., 1993; Murakami et al., 1997). The optimal enzyme reaction occurs under neutral to mildly alkaline conditions (pH ∼ 7–9) in the presence of millimolar Ca2+. Using pure phospholipid vesicles as a substrate, the group II subfamily of sPLA2s prefers anionic phospholipids such as phosphatidylglycerol, phosphatidylethanolamine (PE), and phosphatidylserine (PS) to charge-neutral phosphatidylcholine (PC); sPLA2-X does not discriminate between the head group moieties; and sPLA2-IB exhibits an intermediate pattern. On the basis of the strict lipid–water interfacial studies, sPLA2-IB binds much more tightly to anionic phospholipids than to PC, although the binding to PC is significant (Snitko et al., 1999). Hydrolysis of PC is greatly accelerated, to a level comparable with that of PE, in the presence of a low concentration of detergents such as deoxycholate (Hanasaki et al., 1999; Kudo et al., 1993). sPLA2-IIA binds very weakly to PC vesicles even at millimolar concentrations, and interfacial binding is enhanced by >106-fold when anionic phospholipids are mixed (Kinkaid and Wilton, 1995). sPLA2-IIC, -IID, -IIE, and -IIF exhibit substrate specificity similar to that of sPLA2-IIA (Ishizaki et al., 1999; Murakami et al., 1998; Suzuki et al.,

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2000; Valentin et al., 1999a,b). sPLA2-V binds at least 100-fold more tightly to anionic phospholipid vesicles than to PC vesicles, but binds to the latter with much higher affinity than do sPLA2-IB and -IIA (Han et al., 1999). Paradoxically, AA-containing phospholipids are rather poorer substrates for sPLA2-V than are linoleate-containing phospholipids (Chen and Dennis, 1998; Hanasaki et al., 1999), even though this isozyme has the potent ability to mobilize AA metabolism in mammalian cells (see below). sPLA2-X hydrolyzes PE and PC vesicles in an almost equal ratio (Hanasaki et al., 1999; Murakami et al., 1999c). Sphingomyelin (SM) inhibits the enzymatic activity of sPLA2-IB and -IIA in vitro (Koumanov et al., 1997). The high packing density of lipid bilayers enriched in SM hinders the penetration of sPLA2s into the membrane. Cholesterol counteracts the effect of SM-based inhibition of sPLA2s (Koumanov et al., 1998). Several hydrophobic residues near the -helical N terminus of sPLA2s contribute to interfacial binding to phospholipid vesicles (Murakami et al., 1997). Tryptophan residues located on the putative interfacial binding surfaces are postulated to be critical for penetration of sPLA2 into PC vesicles. Indeed, Trp31 and Trp67 are crucial for the binding of sPLA2-V and sPLA2-X, respectively, to PC vesicles (Bezzine et al., 2000; Han et al., 1999). sPLA2-IIA, which binds very poorly to PC vesicles, does not have such a tryptophan, yet replacement of Val3 by Trp increases the affinity for PC dramatically (Baker et al., 1998). sPLA2IIA, -IID and -V contain a number of basic amino acid residues throughout the molecules, and at least in the case of sPLA2-IIA, some of them contribute to binding to anionic phospholipid vesicles (Koduri et al., 1998). C. HEPARANOID BINDING sPLA2-IIA, -IID, and -V are highly cationic isozymes and bind tightly to heparin–Sepharose, whereas the other sPLA2 isozymes with acidic to neutral pI show no, or very low, affinity (Ishizaki et al., 1999; Murakami et al., 1996, 1998, 1999b,c; Valentin et al., 1999a). An initial site-directed mutagenesis study demonstrated that the cluster of basic amino acids near the C terminus of sPLA2IIA and V plays a crucial role in heparanoid binding (Murakami et al., 1996). Later, it was shown that the affinity of sPLA2-IIA for heparanoids is modulated not only by a highly localized site of basic residues but also by diffuse sites that partially overlap with the interfacial binding site (Koduri et al., 1998). As described below, this heparin-binding property affects the cellular functions of these sPLA2s under various conditions. Heparin and chondroitin sulfate, but not heparan sulfate, increase severalfold the activity of sPLA2-IIA toward lowdensity lipoprotein (Sartipy et al., 1996). On the other hand, heparan sulfate on mast cells plays a negative regulatory role for sPLA2-IIA, in which the enzyme is bound to heparan sulfate on cell surfaces, internalized, and then degraded rapidly (Enomoto et al., 2000b).

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III. Expression and Functions of sPLA2s

A. SPLA2-IB The sPLA2 present in pancreatic juice is classified as sPLA2-IB, and its main role is the digestion of phospholipids in food (Verheij et al., 1981). sPLA2-IB is synthesized in the pancreatic acinar cells, liberated into the pancreatic juice, and secreted into the duodenum. sPLA2-IB in pancreatic tissue exists exclusively as an inactive proenzyme, and removal of an N-terminal heptapeptide by trypsin yields an active enzyme. sPLA2-IB is also expressed in trace amounts in several tissues such as lung, kidney, and spleen (Hara et al., 1995; Tojo et al., 1988), where it is assumed to play nondigestive roles. Plasma plasmin is a possible candidate to promote the conversion of inactive zymogen to mature enzyme in these nondigestive organs (Nakano et al., 1994). Although only limited information about transcriptional regulation of sPLA2-IB is available, expression of sPLA2-IB mRNA in the pancreas is reported to be decreased following excess intake of glucose (Metz et al., 1991). Intact cellular membrane is usually rather resistant to sPLA2-IB–directed hydrolysis (Bezzine et al., 2000; Murakami et al., 1998). This is probably because this isozyme shows poor interfacial binding to PC-rich plasma membrane surfaces and has virtually no affinity for heparan sulfate proteoglycan, which acts as a cell surface adapter for the heparin-binding group II subfamily of sPLA2s (see below). However, as described later in detail, sPLA2-IB binds to the M-type sPLA2 receptor with high affinity, through which it stimulates various cellular responses, including AA release (Lambeau and Lazdunski, 1999). sPLA2-IB has been implicated in the pathogenesis and pathophysiology of acute pancreatitis. The initial enthusiasm concerning pancreatic sPLA2-IB as an enzyme responsible for pancreatic necrosis and systemic manifestations of acute pancreatitis has gradually waned, as the mechanisms of the pathogenesis and pathophysiology of acute pancreatitis have been revealed. The overactive systemic inflammatory response seen in severe acute pancreatitis, associated with the activation of different cascade systems and increased levels of inflammatory mediators, closely resembles that associated with other severe inflammatory diseases (e.g., septic shock). Although activation of sPLA2-IB in the pancreas may cause tissue damage, the elevated serum PLA2 levels in patients with acute pancreatitis are due to sPLA2-IIA, production of which is generally induced during the inflammatory response (see below), rather than to sPLA2-IB that has leaked from the damaged pancreas (Nevalainen et al., 1999). B. SPLA2-IIA 1. Expression Discovery of sPLA2-IIA dates back a decade, when several inflammation researchers succeeded in purification of an sPLA2 distinct from pancreatic sPLA2

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from inflammatory exudates and platelets (Chang et al., 1987; Horigome et al., 1987; Kramer et al., 1989; Seilhamer et al., 1989a). sPLA2-IIA is synthesized as a precursor form containing a signal sequence and is then processed to a mature enzyme during translocation from the cytosolic to the luminal side of the endoplasmic reticulum. Constitutive expression of sPLA2-IIA has been detected in several tissues, such as the spleen, thymus, intestine, tonsil, liver, and bone marrow (Murakami et al., 1997), and also in inflammatory effector cells, such as platelets, neutrophils, macrophages, and mast cells, in which sPLA2-IIA is stored in secretory granules and released into the extracellular fluids immediately after cell activation (Horigome et al., 1987; Murakami et al., 1992). In the intestine, sPLA2-IIA is localized in Paneth cells, where it plays a role in antimicrobial defense (Senegas-Balas et al., 1984); in the liver, it is distributed preferentially in the Kupffer cells (Inada et al., 1991). Large amounts of sPLA2-IIA have been detected at various inflamed sites and in the plasma of patients with rheumatoid arthritis and septic shock, as well as in experimental animal models of inflammation (Kudo et al., 1993; Murakami et al., 1997; Pruzanski and Vadas, 1988; Vadas and Pruzanski, 1986). These findings strongly argue that sPLA2-IIA is involved in inflammatory responses and host defense. Notably, sPLA2-IIA is an inducible isozyme in response to various stimuli (Couturier et al., 1999; Crowl et al., 1991; Kuwata et al., 1998; Murakami et al., 1993a; Nakazato et al., 1991; Oka and Arita, 1991; Pfeilschifter et al., 1993;. Suga et al., 1993). The major inducers of sPLA2-IIA expression include bacterial lipopolysaccharide (LPS); the proinflammatory cytokines, such as interleukin 1 (IL-1), tumor necrosis factor, and IL-6; and cAMP-elevating agents. Cytokineinduced sPLA2-IIA expression occurs in various types of cells, such as chondrocytes, smooth muscle cells, hepatocytes, astrocytes, renal mesangial cells, endothelial cells, mast cells, macrophages, and fibroblasts. The time-dependent induction of sPLA2-IIA expression generally occurs after an initial lag period of several hours and then continues to increase throughout the culture period, accompanied by sustained PG generation. Injection of LPS into rats markedly induces sPLA2-IIA expression in many tissues (Nakano and Arita, 1990; Sawada et al., 1999). The promoter region of the sPLA2-IIA gene contains TATA and CAAT boxes and several elements homologous with consensus sequences for binding of transcription factors such as activator protein-2, nuclear factor–IL-6, nuclear factor-B, and peroxisome proliferator-activated receptor (PPAR)  (Couturier et al., 1999; Crowl et al., 1991). Anti-inflammatory glucocorticoids are potent suppressors of the induction of sPLA2-IIA expression (Kuwata et al., 1998; Nakano and Arita, 1990; Nakano et al., 1990). Transforming growth factor , an anti-inflammatory cytokine, as well as platelet-derived growth factor and insulinlike growth factors also reduce sPLA2-IIA induction, with a concordant decrease in PG generation (Muhl ¨ et al., 1991; Schalkwijk et al., 1992).

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2. Eicosanoid Biosynthesis Arachidonic acid metabolism is subdivided into two phases according to the time courses of the production of particular kinds of eicosanoids, which in turn depend on the type of cell and stimulus involved (Bingham et al., 1996; Murakami et al., 1994, 1997, 1998, 1999a; Reddy and Herschman, 1997; Reddy et al., 1997). Many cells respond to a number of ligands coupled to G proteins or tyrosine kinases, which cause transient intracellular Ca2+ mobilization and elicit “immediate” eicosanoid generation that lasts only for several minutes. Thromboxane A2 generation by platelets and PGD2 and leukotriene C4 generation by mast cells activated with immunoglobulin E and antigen are typical examples of immediate eicosanoid generation utilizing constitutively expressed enzymes for eicosanoid biosynthesis. Another aspect of eicosanoid generation is the “delayed” production of prostanoids following stimulation with cytokines, growth factors, and mitogens that lasts for several hours and is accompanied by de novo synthesis of regulatory proteins. The existence of two kinetically distinct PG-biosynthetic responses, the immediate and delayed phases, implies the recruitment of different sets of biosynthetic enzymes to this pathway. A rapidly expanding body of evidence suggests that the two COX isozymes, the constitutive COX-1 and the inducible COX-2, play distinct roles in regulating AA metabolism (Smith et al., 1996). Generally, utilization of COX-1 is observed during the immediate phase of PG biosynthesis, whereas COX-2–dependent PG generation proceeds over several hours in parallel with the induction of COX-2 expression. Segregated utilization of COX-1 and COX-2 in different phases of the PG-biosynthetic responses depends, at least in part, on the amounts of AA released by PLA2s at the moment when PG generation takes place. At the cellular level, COX-1 requires higher concentrations of AA for its function than does COX-2 (Murakami et al., 1999a; Shitashige et al., 1998). Thus, during the immediate phase, when a burst of AA is released in a short time, the local concentration of AA reaches a level high enough to activate constitutive COX-1, whereas a limited amount of AA is supplied gradually in the delayed phase, during which only inducible COX-2 is active. The fact that the induction of sPLA2-IIA expression is often associated with concomitant changes in COX-2 expression and PG generation implies that this isozyme contributes to supplying AA to COX-2 to promote delayed PG biosynthesis. Support for this speculation was provided by earlier studies using antibodies, chemical inhibitors, and antisense oligonucleotides that were assumed to be specific for sPLA2-IIA (Barbour and Dennis, 1993; Murakami et al., 1993a; Pfeilschifter et al., 1993; Suga et al.,1993). However, the identification of many novel sPLA2 isozymes has forced a reassessment of a significant fraction of the large literature describing the functions of sPLA2-IIA (Tischfield, 1997). Indeed, some of the functions that were ascribed to sPLA2-IIA

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have turned out to be attributable to sPLA2-V, as described below. Nevertheless, recent more careful evaluation of the correlation between expression and function of sPLA2-IIA (Kuwata et al., 1998; Naraba et al., 1998; Tada et al., 1998) has provided unequivocal evidence that this isozyme functions as an amplifier of the delayed PG-biosynthetic response. Cotransfection of sPLA2-IIA and COX-2 in human embryonic kidney 293 cells led to marked augmentation of IL-1–induced delayed AA release and PGE2 generation (Murakami et al., 1998, 1999a–c). Furthermore, coculture of sPLA2-IIA and COX-2 transfectants revealed that extracellular sPLA2-IIA augments PGE2 generation by neighboring COXexpressing cells, implying that it plays a particular role as a mediator of transcellular PG biosynthesis from one cell to another (Murakami et al., 1999a; Tada et al., 1998). Importantly, continuous production and supply of sPLA2-IIA are crucial for it to function appropriately in the delayed PG-biosynthetic response. It is noteworthy that AA release by sPLA2-IIA occurs only when cells are activated by proinflammatory stimuli, whereas quiescent cells are fairly refractory to sPLA2-IIA (Kudo et al., 1993; Murakami et al., 1998). This indicates the existence of regulatory mechanisms that render the membranes susceptible to the action of sPLA2-IIA only after cell activation. The following regulatory mechanisms for the cellular actions of sPLA2-IIA have been proposed. a. Heparan Sulfate Proteoglycan. In many (but not all) cases, the regulatory functions of sPLA2-IIA (as well as other heparin-binding sPLA2s) in the delayed PG-biosynthetic response depend on heparan sulfate proteoglycans, which act as a functional adapter on cell surfaces (Kuwata et al., 1998; Murakami et al., 1993a, 1996, 1998, 1999b; Suga et al., 1993). A considerable portion of de novo– synthesized sPLA2-IIA exists as a cell surface–associated form, which is washed out by extracellular addition of heparin or heparinase. This solubilization process is accompanied by reduction of sPLA2-IIA–mediated PG biosynthesis. Replacement of the C-terminal basic amino acid cluster with acidic amino acids abolishes the ability of sPLA2-IIA to bind heparan sulfate without affecting in vitro enzyme activity, and this particular mutant is incapable of promoting in vivo AA release when transfected into cells (Murakami et al., 1996, 1998). The cell surface heparan sulfate proteoglycans fall into two families of molecules that differ in their core protein domain structures (David, 1993). The syndecans have core proteins with a transmembrane and a cytoplasmic domain, and they possess heparan and/or chondroitin sulfate chains near the N terminus distal to the plasma membrane (Bernfield et al., 1992). The glypicans, by contrast, lack a membrane-spanning domain, are anchored to the external surface of the plasma membrane via glycosylphosphatidylinositol (GPI), and have three heparan sulfate chains near the C terminus, which are close to the plasma membrane (David et al., 1990). Consistent with a GPI-anchored moiety, glypicans are mobile in the cell membrane and exhibit both apical and basolateral distributions, whereas syndecans are distributed basolaterally to be attached to

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extracellular matrix proteins (Mertens et al., 1996). A significant portion of glypican translocates to the nucleus in cells undergoing cell division and activation (Liang et al., 1997). Several lines of evidence have suggested that endogenously expressed sPLA2IIA preferentially associates with the GPI-anchored form of heparan sulfate proteoglycan, glypican (Murakami et al., 1999b). With the aid of glypican, the nanograms per milliliter amount of endogenous sPLA2-IIA that is continuously produced is sufficient to promote AA release. GPI-anchored proteins generally occur in microdomains of the cell membrane called caveolae or the caveolae-related domain (Friedrichson and Kurzchalia, 1998; Hoessli and Robinson, 1998; Smart et al., 1996). Dynamic changes occur in the subcellular distribution of glypican, which moves to the nucleus and punctate caveolaelike domains, depending on cell activation states (Liang et al., 1997). Glypican appears to play a specific role in the sorting of sPLA2-IIA into caveolae-like compartments in activated cells (Murakami et al., 1999b). Caveolae form a unique endocytic and exocytic compartment at the surface of most cells, capable of importing molecules, delivering them to specific locations within the cell, and compartmentalizing a variety of signaling activities (Anderson, 1998). By means of the caveolae-mediated endocytotic event called potocytosis, sPLA2-IIA is capable of being translocated to the perinuclear compartments, in proximity to COX-2 (Murakami et al., 1999b). Since there is considerable evidence to indicate that caveolae are a site of Ca2+ storage and entry into the cell (Anderson, 1998), it is likely that sPLA2-IIA, a Ca2+-dependent enzyme, present inside caveolae signalsomes retains its enzyme activity even after internalization and translocation to the perinuclear domain. The caveolae membrane is enriched in SM, which inhibits the enzymatic activity of sPLA2-IIA in vitro (Koumanov et al., 1997). A decrease in the cellular SM content caused by sphingomyelinase in response to cytokines (Adam-Klages et al., 1996) may allow the otherwise silent sPLA2-IIA to become active toward the caveolae membrane. Cholesterol, which is also abundant in caveolae (Anderson, 1998), counteracts the effect of SMbased inhibition of sPLA2-IIA (Koumanov et al., 1998) and may contribute to the temporal and spatial regulation of this enzyme during cell activation. Studies using a sPLA2-IIA mutant with altered interfacial binding further supported the idea that sPLA2-IIA does not simply act on the PC-rich outer plasma membrane but on a membrane compartment rich in acidic phospholipids in the glypicandependent pathway (Murakami et al., 2001). b. Membrane Asymmetry. That sPLA2-IIA hardly acts on resting cell membranes is likely to be a reflection of its poor interfacial binding capacity to PC, which is enriched in the external surface of the plasma membrane (Baker et al., 1998; Bezzine et al., 2000; Koduri et al., 1998). In order for exogenous sPLA2-IIA to enhance agonist-stimulated AA release, high concentrations of the enzyme (on the order of micrograms per milliliter) are often required (Murakami et al.,

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1997). Mutational analyses have shown that the action of exogenous sPLA2-IIA on cells is transient and depends essentially on its interfacial binding to PC, but not on heparan sulfate binding (Koduri et al., 1998). This notion is further supported by the observations that exogenous sPLA2-X (Bezzine et al., 2000; Hanasaki et al., 1999) and sPLA2-V (Han et al., 1999), which exhibit much higher PC-hydrolytic activity than sPLA2-IIA, elicit AA release at lower concentrations than sPLA2-IIA, even in unstimulated cells. It has been proposed that the transbilayer movement of anionic phospholipids, the preferred substrates for sPLA2-IIA, to the external surface of the plasma membrane is one of the mechanisms underlying increased cellular sensitivity to the enzyme (Kudo et al., 1993; Murakami et al., 1997). Whether perturbed membrane asymmetry indeed influences the cellular actions of sPLA2-IIA has been verified by transfection experiments with phospholipid scramblase, which facilitates the transbilayer movement of anionic phospholipids (Zhao et al., 1998; Zhou et al., 1997). Thus, overexpression of phospholipid scramblase led to exposure of PS on the external surface of the plasma membrane, accompanied by increased cellular susceptibility to sPLA2-IIA, even without cell activation (Murakami et al., 1999c). However, it still remains uncertain whether the phospholipid scramblase–dependent process occurs under physiological conditions. Damaged or apoptotic cell membranes (Atsumi et al., 1997) and microvesicles shed from activated cells (Fourcade et al., 1995), in which PS is exposed to the external surface (Martin et al., 1996), are potential targets for exogenous sPLA2-IIA. c. Oxidation of cPLA2-Derived Products. Several lines of evidence have suggested that cPLA2 is required in order for sPLA2-IIA (and sPLA2-V; see below) to act properly (Kambe et al., 1999; Kuwata et al., 1998; Murakami et al., 1998). Supporting this idea are the observations that sPLA2-IIA-dependent AA release was blocked by cPLA2 inhibitors and restored by supplementation with exogenous AA, and that cotransfection of cPLA2 and sPLA2-IIA augmented AA release in a synergistic manner. cPLA2 is also required in several cell types for the induction of sPLA2-IIA at the transcriptional level by cytokines (Couturier et al., 1999; Kuwata et al., 1998). In the search for a regulatory molecule that links cPLA2 and sPLA2-IIA, 12/15LOX, a LOX isozyme that oxygenates free AA as well as esterified polyunsaturated fatty acids in the cellular membranes (Brash, 1999), has been found to play a pivotal role in the regulation of sPLA2-IIA (Kuwata et al., 2000). 12/15-LOX regulation of sPLA2-IIA occurs in two ways. First, 12/15-LOX–oxidized lipids sensitize the cellular membranes to be more susceptible to sPLA2-mediated AA release. This is compatible with the observations that sPLA2-IIA–mediated hydrolysis is accelerated by chemical oxidization of membranes (Akiba et al., 1997). Second, 12/15-LOX products up-regulate the induction of sPLA2-IIA expression. As the ligands for the nuclear receptor PPAR are fatty acids and their

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oxidized derivatives, including 12/15-LOX metabolites (Huang et al., 1999), the putative PPAR -binding site in the sPLA2-IIA gene promoter region has been suggested to be involved in 12/15-LOX–mediated regulation of sPLA2-IIA expression (Couturier et al., 1999). Thus, cPLA2 activation immediately after cell activation leads to production of 12/15-LOX metabolites, which in turn trigger sensitization of the membranes to be susceptible to sPLA2-IIA–mediated AA release. The AA thus released is further oxidized by 12/15-LOX and contributes to amplification of sPLA2IIA gene transcription and the membrane rearrangement process, leading to sustained activation of sPLA2-IIA and the attendant delayed generation of PG. This scenario has revealed a functional array of enzymes in separate arms of the AA cascade, the LOX and COX pathways, and the biological importance of LOX-directed lipid oxidation signaling in regulating the expression and function of particular lipid-metabolizing enzymes. 3. Antimicrobial Activity Phagocytosis of gram-negative Escherichia coli by neutrophils, which is an essential first-line defense against invading bacteria, triggers bacterial envelope phospholipid degradation; the extent of intracellular destruction of these ingested bacteria is closely linked to the magnitude of PLA2 action (Elsbach and Weiss, 1988). sPLA2-IIA participates in intracellular bacterial digestion by associating with the surfaces of bacteria and neutrophils before phagocytosis and acting after co-internalization with ingested bacteria (Wright et al., 1990). Although sPLA2-IIA alone cannot manifest antimicrobial activity directly by degrading the phospholipids in intact bacterial membranes, in combination with a neutrophilderived protein called bactericidal permeability–increasing protein (BPI) it reduces the viability of microorganisms (Wright et al., 1990). In the presence of BPI, phospholipids in intact bacteria are hydrolyzed by sPLA2-IIA both extracellularly and intracellularly. sPLA2-IB is unresponsive to BPI, although both isozymes show virtually the same activity toward E. coli phospholipids after the bacterial structure has been altered by autoclaving or after extraction. The clusters of basic residues (Arg7, Lys10, and Lys15) in the N-terminal region of human sPLA2-IIA may account, in part, for its ability to act on BPI-treated bacterial membranes (Weiss et al., 1991). The close correlation between the effects of these mutations on BPI-dependent PLA2 binding and hydrolytic activity toward E. coli suggests that a major role of these basic residues is to mediate electrostatic interactions with acidic bacterial envelope sites that become available after BPI treatment, as well as hydrogen bond–mediated interactions. The bactericidal activity of intestinal sPLA2-IIA, which is produced by Paneth cells, may play a crucial role in protecting the small intestinal crypts from microbial invasion (Harwig et al., 1995).

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A biological role for sPLA2-IIA in contributing to the antimicrobial arsenal mobilized by the host in response to invading microorganisms has been established by several studies using sPLA2-IIA transgenic mice. These mice exhibit epidermal and adnexal hyperplasia, hyperkeratosis, and almost total alopecia (Grass et al., 1996). The chronic epidermal hyperplasia and hyperkeratosis seen in these mice is similar to that seen in a variety of dermatopathies, including psoriasis. After the administration of Staphylococcus aureus or E. coli, the transgenic mice showed reduced mortality, improved resistance, and increased bacterial killing (Laine et al., 1999, 2000). 4. Anticoagulation The anticoagulant activities of the sPLA2 family depend on the presence of basic residues within a specific variable surface region (residues 54–77) distinct from both the conserved catalytic machinery and the surface sites mediating the antimicrobial action of these enzymes (Kini and Evans, 1987). Substitution of Lys56 by Gln in human sPLA2-IIA reduced, whereas that of Asp59 by Arg and Ser60 by Gly in porcine sPLA2-IB increased, the anti-prothrombinase activity of the enzyme (Inada et al., 1994), providing the first direct evidence for a role of basic residues within this region in the effects of sPLA2 against reactions that promote coagulation. The anticoagulation effect can occur independently of the presence of phospholipids but requires factor Va, leading to the hypothesis that sPLA2-IIA inhibits this factor (Mounier et al., 1996). In addition to the noncatalytic and phospholipid-independent component, the degradation of PS, an essential component of the prothrombinase complex, also plays an important role in the inhibition of prothrombinase by sPLA2IIA. The role of sPLA2-IIA released from activated platelets is more likely to regulate the clotting reaction negatively by degrading PS, thereby suppressing prothrombinase complex formation on platelet membranes and microvesicles (Fourcade et al., 1995; Yokoyama et al., 1995), rather than by contributing to thromboxane A2 biosynthesis, leading to acceleration of coagulation (Mounier et al., 1993). sPLA2-IIA also potentiates PGI2 generation by vascular endothelial cells (Murakami et al., 1993a), further implying its potential role as a negative regulator of blood coagulation. 5. Degranulation Several pharmacological and immunochemical studies have suggested the participation of sPLA2 in exocytosis of several endocrine cells, including mast cells and chromaffin cells (Matsuzawa et al., 1996; Murakami et al., 1992). sPLA2-IIA added exogenously at high concentrations directly elicited degranulation of rat peritoneal mast cells (Murakami et al., 1993b). Direct evidence for the involvement of sPLA2-IIA in mast cell degranulation has been provided

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by transfection studies, where immunoglobulin E–dependent degranulation of rat mastocytoma RBL-2H3 cells was markedly augmented by overexpression of sPLA2-IIA (Enomoto et al., 2000a). sPLA2-IIA, which is stored in secretory granules in unstimulated cells, accumulates on the membranous sites where the fusion between the plasma membrane and granule membranes occurs in activated cells. As the lysophospholipid perturbs the structure of bilayer membranes (Karli et al., 1990), its production around the opening granular membranes by the enzymatic action of sPLA2-IIA may facilitate the ongoing membranefusion. 6. Pathology a. Inflammation. Detection of high levels of sPLA2-IIA at various inflamed sites suggests that it is involved in pathogenesis of the inflammatory responses (Kudo et al., 1993). The pathological roles of sPLA2-IIA in local inflammatory processes have been confirmed by injecting purified or recombinant sPLA2-IIA into different sites of experimental animals (Bomalaski et al., 1991; Murakami et al., 1990) or by administering particular inhibitors or antibodies that are fairly specific for sPLA2-IIA into various inflamed sites (Fleisch et al., 1996; GarciaPastor et al., 1999; Kakutani et al., 1994; Marshall et al., 1995; Snyder et al., 1999; Tanaka et al.,1994). It should be noted, however, that the latter observations may be due to inhibition of sPLA2 isozymes other than sPLA2-IIA, particularly in studies using mice as an experimental model, where the expression of sPLA2-IIA is limited to the intestine, whereas that of sPLA2-V is ubiquitous and inducible (Sawada et al., 1999). b. Ischemia. PLA2-induced changes in phospholipid integrity and the toxic actions of free fatty acids and lysophospholipids may be critical for the altered plasma membrane and mitochondrial permeability properties and bioenergetic capacity associated with ischemia and perfusion. Activation of sPLA2-IIA is associated with ischemia and related tissue injury (Hatch et al., 1993; KikuchiYanoshita et al., 1993; Koike et al., 1995; Lauritzen et al., 1994). Antibodies against sPLA2-IIA prevented renal injury due to ischemia and reperfusion in rats (Takasaki et al., 1998). c. Atherosclerosis. Studies using sPLA2-IIA transgenic mice have revealed its unexplored role in the development of atherosclerosis (Ivandic et al., 1999; Leitinger et al., 1999; Tietge et al., 2000). The transgenic mice exhibited increased atherosclerotic lesions, around which sPLA2-IIA accumulated. sPLA2IIA may promote atherogenesis, in part, through decreasing high-density lipoprotein levels. Furthermore, the levels of biologically active oxidized phospholipids are increased in sPLA2-IIA transgenic mice. The correlation between the expression of sPLA2-IIA and the degree of atherosclerosis underlines its possible importance in atherogenesis (Schiering et al., 1999).

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d. Cancer. The sPLA2-IIA gene is naturally disrupted by a frameshift mutation in exon 3 in some inbred mouse strains (Kennedy et al., 1995; MacPhee et al., 1995). The lack of observable differences in the physiology and pathology of sPLA2-IIA–deficient and normal mouse strains suggests that sPLA2s are redundant in mammals and that other isozymes can compensate for loss of sPLA2-IIA. Mutations in the APC gene are responsible for various familial and sporadic colorectal cancers. Min mice carrying a dominant mutation in the homologue of the APC gene develop multiple adenomas throughout their small and large intestines. Of particular importance, the gene for mouse sPLA2-IIA maps to the Mom1 locus in the distal region of chromosome 4 that dramatically modifies Min-induced tumor number (MacPhee et al., 1995). Thus, sPLA2-IIA is a candidate for modifier of polyp numbers by altering the cellular microenvironment within the intestinal crypts. The most likely explanation for this is that the presence of wild-type sPLA2-IIA activity confers resistance to multiple adenoma formation, whereas the truncated product has no effect on tumor formation. In marked contrast to the situation in the mouse model, however, sPLA2-IIA gene mutations do not appear to play a major role in the development of colorectal cancer in humans (Riggins et al., 1995). Rather, the high level of sPLA2-IIA expression often detected in human familial adenomatous polyposis is more likely to contribute to the elevated levels of AA found in colorectal cancer and, in conjunction with the elevated expression of COX-2, which is crucially involved in tumorigenesis (Oshima et al., 1996), could be another factor in tumor formation (Kennedy et al., 1998). In relation to this, overexpression of sPLA2-IIA prevents apoptosis in certain cell lines (Zhang et al., 1999). Although the reason that sPLA2-IIA has an antitumorigenic potential in mice is still unclear, mechanisms other than prostanoid generation may be involved. The lack of bactericidal sPLA2-IIA in the intestine may enable proliferation of certain types of bacteria that produce carcinogenic products facilitating the formation of polyps and malignant transformation. Alternatively, loss of asymmetry in colon cancer cells leads to increased accessibility to cell membrane phospholipids, providing a suitable target for sPLA2-IIA membrane hydrolysis. In support of this idea, cotransfection of sPLA2-IIA and phospholipid scramblase, which disturbs membrane asymmetry, into 293 cells led to marked reduction in cell growth, accompanied by increased membrane hydrolysis (Murakami et al., 1999c). C. SPLA2-V 1. Expression sPLA2-V appears to be a primary sPLA2 isozyme in mice, where its mRNA is detected in a wide variety of tissues and cells, whereas its expression is rather restricted to the heart and, to a lesser extent, to the lung in humans and rats (Chen et al., 1994a; Sawada et al., 1999). Conversely, sPLA2-IIA is widely distributed in humans and rats, whereas it is detected only in the intestine of mice. Injection of LPS increases sPLA2-V expression in various organs in mice and in the heart in

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rats (Sawada et al., 1999). Stimulation of mouse macrophage-like P388D1 cells with LPS (Shinohara et al., 1999) and mouse cultured mast cells with particular combinations of cytokines (Sawada et al., 1999) results in marked up-regulation of sPLA2-V expression. Therefore, it is likely that sPLA2-V in mice takes the place of sPLA2-IIA in rats and humans under various conditions. 2. Functions sPLA2-V is constitutively expressed in mouse macrophage-like P388D1 cells (Balboa et al., 1996; Balsinde and Dennis, 1996; Balsinde et al., 1998) and mouse mast cells (Reddy and Herschman, 1997; Reddy et al., 1997; Sawada et al., 1999), in which it plays a role in augmentation of immediate PGE2 production induced by PAF following LPS priming and immunoglobulin E–dependent immediate PGD2 production, respectively. Inducible sPLA2-V promotes LPS-induced delayed PGE2 generation in P388D1 cells (Shinohara et al., 1999). Transfection of sPLA2-V into 293 cells and Chinese hamster ovary (CHO) cells led to increases in both the immediate and delayed phases of AA release elicited by appropriate stimuli (Murakami et al., 1998). AA released by sPLA2-V is converted to PGs via both COX-1 and COX-2 in the immediate response and predominantly by COX-2 in the delayed response (Balsinde et al., 1998; Murakami et al., 1999a; Reddy and Herchman, 1997; Reddy et al., 1997; Sawada et al., 1999; Shinohara et al., 1999). sPLA2-V is also capable of promoting transcellular PG biosynthesis (Murakami et al., 1999a; Reddy and Herschman, 1996). Prior activation of cPLA2 is necessary for sPLA2-V to act (Balsinde et al., 1998; Shinohara et al., 1999). All of these functional features of sPLA2-V are very similar to those of sPLA2-IIA (see above). Moreover, both sPLA2-IIA and -V have the ability to increase COX-2 expression, which further contributes to augmentation of delayed PG generation (Balsinde et al., 1999; Murakami et al., 1999c; Tada et al., 1998). Consistent with these close similarities, sPLA2-V, like sPLA2-IIA, utilizes the glypican-dependent route for the promotion of delayed PG biosynthesis (Murakami et al., 1999a, 2001). Collectively, these findings imply that both isozymes are functionally compensatory. However, several studies have suggested that the functions of sPLA2-IIA and -V are not perfectly identical. When sPLA2-V was overexpressed in RBL2H3 cells, it markedly augmented immunoglobulin E–dependent immediate PGD2 and leukotriene C4 generation and degranulation, whereas sPLA2-IIA augmented degranulation (see above) without affecting eicosanoid biosynthesis (Enomoto et al., 2000a; Murakami et al., 2001; Sawada et al., 1999). Exogenously added sPLA2-V, but not -IIA, directly promoted leukotriene B4 generation in human neutrophils (Han et al., 1999). In mouse P388D1 macrophages, exogenous sPLA2-V was capable of eliciting AA release even without additional stimuli (Balsinde et al., 1999), whereas exogenous sPLA2-IIA required appropriate costimulators to do so (Balsinde et al., 1998). The more potent eicosanoidbiosynthetic action of sPLA2-V than that of sPLA2-IIA in these settings is most

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probably because the former enzyme has much higher PC-hydrolytic activity than the latter (Han et al., 1999). Thus, when acting on the outer leaflet of the plasma membrane independently of glypican, the cellular action of sPLA2-V depends essentially on its interfacial binding ability to PC, on which sPLA2-IIA is unable to act. In this regard, sPLA2-V behaves like sPLA2-X (see below). In mouse mast cells, sPLA2-IIA is stored in secretory granules, whereas sPLA2-V is distributed mainly in intracellular compartments such as the Golgi apparatus and perinuclear membranes (Bingham et al., 1999). Such a different subcellular localization in the same cell also suggests their functional segregation under certain conditions. D. OTHER MEMBERS OF THE GROUP II SUBFAMILY OF SPLA2S sPLA2-IIC is expressed in rat and mouse testis, but is a pseudogene in humans (Chen et al., 1994b; Tischfield, 1997). In mouse testis, sPLA2-IIC is expressed in cells undergoing meiosis, including pachytene spermatocytes, secondary spermatocytes, and round spermatids (Chen et al., 1997). sPLA2-IIC has little affinity for heparanoids and is unable to promote AA release when overexpressed in 293 cells (Murakami et al., 1998). sPLA2-IID, -IIE, and -IIF were identified during the searches of DNA databases for expressed sequence tags representing parts of genes for sPLA2 homologues. sPLA2-IID shows high homology (48%) with sPLA2-IIA, and its expression is detected in several tissues, including spleen, thymus, skin, lung, ovary, and colon (Ishizaki et al., 1999; Valentin et al., 1999a). The expression of sPLA2-IID is elevated in the thymus after treatment with LPS (Ishizaki et al., 1999). As in the case of sPLA2-IIA and -V, overexpression of sPLA2-IID in 293 cells augments agonist-induced immediate and delayed AA release and attendant PGE2 generation, which occurs through the glypican shuttling mechanism (Murakami et al., 2001). sPLA2-IIE shows the highest homology (51%) with sPLA2-IIA (Suzuki et al., 2000; Valentin et al., 1999b). The enzymatic properties of human sPLA2-IIE are almost identical to those of sPLA2-IIA and -IID, whereas the mouse orthologue exhibits very low enzymatic activity. In contrast to the broad expression profiles of sPLA2-IIA and -IID, the expression of sPLA2-IIE is restricted to the brain, heart, placenta, and uterus and is markedly enhanced in the lung and intestine following LPS challenge. sPLA2-IIE is expressed in alveolar macrophages in the lungs of LPS-treated mice. The genomic organizations of sPLA2-IIA, -IID and -IIE are almost identical, revealing their evolutionary conservation (Suzuki et al., 2000). sPLA2-IIF, which has a unique long C-terminal extension, is strongly expressed during embryogenesis and in adult testis of mice (Valentin et al., 1999b). Like the other members of the group II subfamily of sPLA2s, sPLA2-IIF hydrolyzes anionic phospholipids in preference to PC in vitro. The functions of sPLA2-IIE and -IIF have yet to be elucidated.

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E. SPLA2-X 1. Expression sPLA2-X is produced as a zymogen with weak catalytic activity, and a propeptide composed of 11 amino acids is removed during the secretion process to produce an active mature enzyme (Hanasaki et al., 1999). Human sPLA2-X is expressed in several organs and tissues related to the inflammatory response, such as spleen, thymus, and peripheral blood leukocytes (Cupillard et al., 1997). In human lung, sPLA2-X is expressed in alveolar epithelial cells (Hanasaki et al., 1999). In contrast, its expression in mice is restricted to the testis and the stomach (Valentin et al., 1999b). 2. Functions sPLA2-X is able to hydrolyze PC much more efficiently than any other mammalian sPLA2 isozymes identified to date (Bezzine et al., 2000; Hanasaki et al., 1999; Murakami et al., 1999c). Although sPLA2-X does not bind heparan sulfate appreciably and is therefore secreted into the supernatant without being retained on cell surfaces when overexpressed in 293 cells, it is capable of promoting fatty acid release even in the absence of stimulus (Murakami et al., 1999c). Exogenous sPLA2-X is also strongly active on mammalian cells, releasing fatty acids even from cells that are refractory to sPLA2-IB, -IIA, -IID and even -V (Bezzine et al., 2000; Hanasaki et al., 1999). The cellular action of sPLA2-X apparently occurs through randomly hydrolyzing PC in the outer leaflet of the plasma membrane. The AA released by sPLA2-X is converted to PGE2 mainly via COX-2 (Bezzine et al., 2000; Murakami et al., 1999c). F. SPLA2-III So far, structurally related groups I and II sPLA2s have been found in vertebrates such as mammals and snakes, whereas group III sPLA2s have mainly been found in venom from invertebrates such as bees and scorpions. cDNA coding for a novel human sPLA2 that displays 31% homology with bee venom group III enzyme has been identified (Valentin et al., 2000). The full-length human sPLA2-III cDNA codes for a signal peptide of 19 residues followed by a protein of 490 amino acids made up of a central sPLA2 domain (141 residues) flanked by large N- and C-terminal regions (130 and 219 residues, respectively). The sPLA2 domain displays all of the features of group III sPLA2s, including 10 cysteines. The sPLA2-III gene maps to chromosome 22. The sPLA2-III transcript is found in kidney, heart, liver, and skeletal muscle. sPLA2-III shows an 11-fold preference for phosphatidylglycerol over PC and optimal activity at pH 8. The function of sPLA2-III remains to be elucidated.

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IV. sPLA2 Receptors

Venom sPLA2s display different types of toxicity, including neurotoxicity, myotoxicity, and anticoagulant and proinflammatory effects, and these varying effects are linked to the existence of a variety of high-affinity receptors for these toxic enzymes. The N-type sPLA2 receptor, initially identified in brain and then in other tissues, recognizes several neurotoxic sPLA2s for which it shows high affinity (Lambeau et al., 1989). The M-type receptor represents another class of sPLA2 receptor, initially identified in skeletal muscle, for myotoxic sPLA2s (Lambeau et al., 1990). The M-type sPLA2 receptor is a 180-kDa type I transmembrane protein with an NH2-terminal cysteine-rich domain, a fibronectin type II domain, eight repeats of a carbohydrate recognition domain (CRD), and transmembrane and cytoplasmic domains, and its entire structure is related to the macrophage mannose receptor (Ishizaki et al., 1994; Lambeau et al., 1994). These characteristics are the first definitive demonstration that sPLA2 has a function unrelated to its phospholipid-hydrolyzing activity. The rabbit sPLA2 receptor binds both human sPLA2-IB and -IIA, and the mouse receptor binds both mouse sPLA2-IB and IIA with high affinity; this contrasts with the receptors of other animal species, including humans, rats, and cows, which are fairly specific for sPLA2-IB (Cupillard et al., 1999). sPLA2-X reportedly acts as a ligand for the receptor (Morioka et al., 2000) whereas sPLA2-IID does not (Valentin et al., 1999a). However, whether other sPLA2 isozymes bind to this receptor is still largely obscure. Alternative splicing of the receptor transcript results in production of a soluble sPLA2 receptor that lacks a transmembrane domain, but still binds to sPLA2-IB with high affinity (Ancian et al., 1995). The human sPLA2 receptor gene maps in the q23–q24 bands of chromosome 2 (Ancian et al., 1995) and has a similar exon–intron structure to the mannose receptor gene (Ishizaki et al., 1994; Lambeau et al., 1994). sPLA2 receptor mRNA is expressed in several tissues, including pancreas, liver, lung, kidney, and spleen, where sPLA2-IB is detectable, although the tissue distributions of the receptor and ligand differ considerably among animal species (Higashino et al., 1994). The N-terminal region of the M-type receptor, including the CRD, is responsible for binding of sPLA2-IB (Kd ∼ 1–10 nM). The domains surrounding CRD4 to CRD6, particularly CRD5, are essential for sPLA2 binding to its receptor (Nicolas et al., 1995). Residues within or close to the Ca2+-binding loop (Gly30, Leu31, and Asp49) of sPLA2-IB are crucial for the binding step, although the presence of Ca2+, which is essential for enzymatic activity, is not required for binding to the receptor (Lambeau et al., 1995). The N-terminal -helices and the pancreatic loop are not essential for binding of sPLA2-IB to the receptor. The sPLA2 receptor undergoes rapid internalization, which is mediated by a clathrin-coated pit and independent of ligand binding (Zvaritch et al., 1996).

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The NSYY motif in the cytoplasmic domain encodes the major endocytic signal, with the distal tyrosine residue playing the key role. Although the importance of sPLA2 receptor internalization remains obscure, it has been proposed that it terminates the signals produced by sPLA2 on target cells, that it serves as a system delivering sPLA2 to specific intracellular components where the ligand can manifest its enzymatic activity, and that it serves a clearance function by selectively removing sPLA2 from the extracellular fluid. M-type sPLA2 receptor knockout mice are viable, fertile, and without evident histopathological abnormalities (Hanasaki et al., 1997). There is no difference in clearance of circulating sPLA2-IB. After challenge with LPS, these mice exhibit longer survival than wild-type mice. The increase in tumor necrosis factor and IL-1 in plasma after LPS treatment is significantly attenuated in the mutant mice. These findings suggest a potential role of sPLA2 receptor in the progression of endotoxin shock. Cross-talk of sPLA2-IB to other PG-biosynthetic enzymes via the M-type sPLA2 receptor, leading to enhanced PG biosynthesis, has been demonstrated (Kishino et al., 1994; Tohkin et al., 1993). sPLA2-IB elicited PGE2 generation by inducing COX-2 in osteoblastic cells (Tohkin et al., 1993) and sPLA2-IIA in renal mesangial cells (Kishino et al., 1994). Activation of cPLA2 by sPLA2s via the sPLA2 receptor–mediated process has been also suggested (Fonteh et al., 1998; Hernandez et al., 1998). Therefore, sPLA2-IB–induced PG biosynthesis depends on de novo protein synthesis and transmembrane signaling through its receptor, rather than direct hydrolysis of membrane phospholipids by its own enzymatic activity. The molecular nature of the N-type sPLA2 receptor is unclear. Photoaffinity labeling and chemical cross-linking techniques have identified a few binding proteins for some snake venom neurotoxic sPLA2s, and one subunit of the binding proteins for several venom sPLA2s is a 45-kDa polypeptide distributed preferentially in neuronal membranes (Yen and Tzeng, 1991). Tyr22 of neurotoxic sPLA2s is essential for the enzymes to bind to this 45-kDa protein, to which sPLA2-IB cannot bind, but substitution of Phe22 by Tyr resulted in sPLA2-IB’s acquiring the capacity to do so (Tzeng et al., 1995). More recently, a novel sPLA2 receptor immunochemically distinct from the M-type receptor has been identified and partially purified from porcine cerebral cortex (Copic et al., 1999). V. Conclusion

With the cloning of ten sPLA2s, it is obvious that a diversity of sPLA2s exists in mammals. These sPLA2s exhibit different tissue distributions and inducibility by stimuli, which also differ according to animal species. The expression levels of these sPLA2s are not the same; to date, numerous expressed sequences tags have been identified for sPLA2-IIA and -IB (Valentin et al., 1999b), indicating

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that these two isozymes are widespread and overwhelming in amount compared with the other recently identified isozymes in rats and humans. The functions of sPLA2s are to regulate the release of lipid mediators in different tissues and cells, acting on various phospholipid substrates, extracellularly or within different cellular compartments, and under physiological and pathological conditions. In regulating AA release from live cells, sPLA2s can utilize both the heparan sulfate–dependent and lipid interface–dependent pathways according to the type and activation state of the cell, as well as the molecular properties, subcellular locations, and dynamics of each isozyme. Moreover, sPLA2s can function not only as enzymes but also as ligands. Further work is clearly needed to understand the biological functions of the different members of the growing family of sPLA2s. REFERENCES Adam-Klages, S., Adam, D., Wiegmann, K., Struve, S., Kolanus, W., Schneider-Mergener, J., and Kronke, M. (1996). FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell 86, 937–947. Akiba, S., Nagatomo, R., Hayama, M., and Sato, T. (1997). Lipid peroxide overcomes the inability of platelet secretory phospholipase A2 to hydrolyze membrane phospholipids in rabbit platelets. J. Biochem. (Tokyo) 122, 859–864. Ancian, P., Lambeau, G., Mattei, M. G., and Lazdunski, M. (1995). The human 180–kDa receptor for secretory phospholipases A2: Molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. J. Biol. Chem. 270, 8963–8970. Anderson, R. G. W. (1998). The caveolae membrane system. Annu. Rev. Biochem. 67, 199–225. Atsumi, G., Murakami, M., Tajima, M., Shimbara, S., Hara, N., and Kudo, I. (1997). The perturbed membrane of cells undergoing apoptosis is susceptible to type II secretory phospholipase A2 to liberate arachidonic acid. Biochim. Biophys. Acta 1349, 43–54. Baker, S. F., Othman, R., and Wilton, D. C. (1998). Tryptophan-containing mutant of human (group IIa) secreted phospholipase A2 has a dramatically increased ability to hydrolyze phosphatidylcholine vesicles and cell membranes. Biochemistry 37, 13203–13211. Balboa, M. A., Balsinde, J., Winstead, M. V., Tischfield, J. A., and Dennis, E. A. (1996). Novel group V phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 macrophages. J. Biol. Chem. 271, 32381–32384. Balsinde, J., and Dennis, E. A. (1996). Distinct roles in signal transduction for each of the phospholipase A2 enzymes present in P388D1 macrophages. J. Biol. Chem. 271, 6758–6765. Balsinde, J., Balboa, M. A., and Dennis, E. A. (1997). Antisense inhibition of group VI Ca2+independent phospholipase A2 blocks phospholipid fatty acid remodeling in murine P388D1 macrophages. J. Biol. Chem. 272, 29317–29321. Balsinde, J., Balboa, M. A., and Dennis, E. A. (1998). Functional coupling between secretory phospholipase A2 and cyclooxygenase-2 and its regulation by cytosolic group IV phospholipase A2. Proc. Natl. Acad. Sci. USA 95, 7951–7956. Balsinde, J., Shinohara, H., Lefkowitz, L. J., Johnson, C. A., Balboa, M. A., and Dennis, E. A. (1999). Group V phospholipase A2–dependent induction of cyclooxygenase-2 in macrophages. J. Biol. Chem. 274, 25967–25970. Barbour, S. E., and Dennis, E. A. (1993). Antisense inhibition of group II phospholipase A2 expression blocks the production of prostaglandin E2 by P388D1 cells. J. Biol. Chem. 268, 21875– 21882.

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