Cloning and Characterization of Novel Mouse and Human Secretory Phospholipase A2s

Abstract

Mammalian secretory phospholipase A2s (sPLA2s) are classified into several groups according to molecular structure and the localization of intramolecular disulfide bridges. Among them, group IIA sPLA2 has been thought to be one of the key enzymes in the pathogenesis of inflammatory diseases owing to its augmented expression under various inflammatory conditions. However, in a number of inbred mouse strains, the group IIA sPLA2 gene is naturally disrupted by a frameshift mutation. Here, we report the cloning of a cDNA encoding a novel sPLA2 expressed in the spleen of group IIA sPLA2-deficient mouse. We also cloned its human homolog and mapped its gene location on chromosome 1p36.12 near the loci of group IIA and V sPLA2 genes. The human mature sPLA2 protein consists of 125 amino acids (Mr = 14,500) preceded by a 20-residue prepeptide and is most similar to group IIA sPLA2 with respect to the number and positions of cysteine residues as well as overall identity (48%). Based on these structural properties, the novel sPLA2 should be categorized into group II, called group IID to follow the already identified IIA to IIC sPLA2s. When the cDNA was expressed in COS-7 cells, PLA2 activity preferentially accumulated in the culture medium. It is maximally active at neutral to alkaline pH and with 2 mm Ca2+. In assays with individual substrates,l-α-1-palmitoyl-2-linoleoyl phosphatidylethanolamine was more efficiently hydrolyzed than the other phospholipids examined. An RNA blot hybridized with the cDNA exhibited two transcripts (2.0 and 1.0 kb) in human spleen, thymus, and colon. The expression of a novel sPLA2 mRNA was elevated in the thymus after treatment with endotoxin in rats as well as in group IIA sPLA2-deficient mice, suggesting its functional role in the progression of the inflammatory process. Mammalian secretory phospholipase A2s (sPLA2s) are classified into several groups according to molecular structure and the localization of intramolecular disulfide bridges. Among them, group IIA sPLA2 has been thought to be one of the key enzymes in the pathogenesis of inflammatory diseases owing to its augmented expression under various inflammatory conditions. However, in a number of inbred mouse strains, the group IIA sPLA2 gene is naturally disrupted by a frameshift mutation. Here, we report the cloning of a cDNA encoding a novel sPLA2 expressed in the spleen of group IIA sPLA2-deficient mouse. We also cloned its human homolog and mapped its gene location on chromosome 1p36.12 near the loci of group IIA and V sPLA2 genes. The human mature sPLA2 protein consists of 125 amino acids (Mr = 14,500) preceded by a 20-residue prepeptide and is most similar to group IIA sPLA2 with respect to the number and positions of cysteine residues as well as overall identity (48%). Based on these structural properties, the novel sPLA2 should be categorized into group II, called group IID to follow the already identified IIA to IIC sPLA2s. When the cDNA was expressed in COS-7 cells, PLA2 activity preferentially accumulated in the culture medium. It is maximally active at neutral to alkaline pH and with 2 mm Ca2+. In assays with individual substrates,l-α-1-palmitoyl-2-linoleoyl phosphatidylethanolamine was more efficiently hydrolyzed than the other phospholipids examined. An RNA blot hybridized with the cDNA exhibited two transcripts (2.0 and 1.0 kb) in human spleen, thymus, and colon. The expression of a novel sPLA2 mRNA was elevated in the thymus after treatment with endotoxin in rats as well as in group IIA sPLA2-deficient mice, suggesting its functional role in the progression of the inflammatory process. phospholipase A2 secretory PLA2 expressed sequence tag polymerase chain reaction base pairs lipopolysaccharide phosphatidylcholine phosphatidylethanolamine phosphatidylserine phosphatidic acid phosphatidylglycerol kilobase(s) Phospholipase A2(PLA2)1 comprises a diverse family of lipolytic enzymes that hydrolyze the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acid and lysophspholipids (1Vadas P. Pruzanski W. Lab. Invest. 1986; 55: 391-404PubMed Google Scholar, 2Arita H. Nakano T. Hanasaki K. Prog. Lipid Res. 1989; 28: 273-301Crossref PubMed Scopus (161) Google Scholar). PLA2s participate in a wide variety of physiological processes, including phospholipid digestion, remodeling of cell membranes, and host defense, and also take part in pathophysiological processes by producing precursors of various types of biologically active lipid mediators, such as prostaglandins, leukotrienes, thromboxanes, and platelet-activating factor (3Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar). Over the past two decades along with advances in molecular biology, numerous PLA2s have been identified and characterized (4Seilhamer J.J. Pruzanski W. Vadas P. Plant S. Miller J.A. Kloss J. Johnson L.K. J. Biol. Chem. 1989; 264: 5335-5338Abstract Full Text PDF PubMed Google Scholar, 5Kramer R.M. Hession C. Johansen B. Hayes G. McGray P. Chow E.P. Tizard R. Pepinsky R.B. J. Biol. Chem. 1989; 264: 5768-5775Abstract Full Text PDF PubMed Google Scholar, 6Clark J.D. Lin L.-L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. 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Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 13Underwood K.W. Song C. Kriz R.E. Chang X.J. Knopf J.L. Lin L.-L. J. Biol. Chem. 1998; 273: 21926-21932Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). According to their biochemical features such as cellular localization, requirement of Ca2+, substrate specificity, and the primary structure, these PLA2s are classified into several families, including low molecular weight secretory PLA2 (sPLA2), Ca2+-sensitive arachidonoyl-specific 85-kDa cytosolic PLA2, Ca2+-independent PLA2, and platelet-activating factor-acetylhydrolase (14Dennis E.A. Trends Biol. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (758) Google Scholar). Low molecular mass sPLA2s (13–18 kDa) have several features distinct from other PLA2 families, such as a high disulfide bond content, a requirement for millimolar concentration of Ca2+ for catalysis, and a broad specificity for phospholipids with different polar head groups and fatty acyl chains (15Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). At present, mammalian sPLA2s are classified into five different groups (groups IB, IIA, IIC, V, and X), depending on the primary structure characterized by the number and positions of cysteine residues (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 14Dennis E.A. Trends Biol. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (758) Google Scholar). Among them, group IIA sPLA2 has been a focus of attention as a potent mediator of the inflammatory process, because its local and systemic levels are elevated in numerous inflammatory diseases, including sepsis, Crohn's disease, and acute pancreatitis (16Gronroots J.M. Nevalainen T.J. PubMed Scopus Google Scholar, R. R. 1991; PubMed Scopus Google and well with in W. B. C. Vadas P. J. Google Scholar). the expression of group IIA sPLA2 is by inflammatory such as and as well as lipopolysaccharide in various cell types R.M. T.J. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, T. H. H. PubMed Scopus Google Scholar, J. Nakano T. H. H. Res. PubMed Scopus Google Scholar, M. Inoue K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In inbred mouse strains, the group IIA sPLA2 gene is by a M. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, P. J. Vadas P. Pruzanski W. M. C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). are to in PubMed Scopus Google Scholar, J.M. A. C.S. J. Google and the from these to Tischfield J.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). The the human group IIA sPLA2 gene inflammatory R.E. Nevalainen T.J. J. Invest. 1996; PubMed Scopus Google Scholar). to the to the of group IIA sPLA2 in inflammatory diseases and that other types of the sPLA2 a role in of in with the group IIA group V one of the identified J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google has been to be in the of lipid in and on Tischfield J.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Tischfield J.A. E.A. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). The most identified group sPLA2 (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google is The of group sPLA2 in inflammatory is by its expression in such as the spleen and thymus, is for its to the conditions. of the of the most group in the inflammatory is also sPLA2 has been thought to as a its in including the W. PubMed Scopus Google Scholar). However, a of have group various such as cell and lipid mediator the to its the H. Hanasaki K. Nakano T. S. H. K. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, K. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. J. J. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. K. R.M. H. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, J. Hanasaki K. K. J. N. H. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, J. H. Prog. Lipid Res. 1995; PubMed Scopus Google Scholar). with for PLA2 and group IIA a role of group in the progression of because the to with levels of inflammatory K. Y. J. T. H. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). identified other low molecular weight PLA2s have been in various including the and J. PubMed Scopus Google suggesting the of novel sPLA2s that a role for the in group IIA sPLA2 functional role in the inflammatory a of the we expressed sequence tag that part of a Here, we report the cloning of a cDNA encoding a novel sPLA2 expressed in the spleen of group IIA sPLA2-deficient We also the cloning of its human the of protein and its expression in as well as in rats and group IIA sPLA2-deficient from was from was from and was from human group IIA sPLA2 was a from and from and from on the cDNA and by the of the was J. Miller W. Res. 1997; PubMed Scopus Google acid sequence the of the mouse group IIA sPLA2 P. J. Vadas P. Pruzanski W. M. C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). cDNA to the identified sequence was by polymerase chain reaction for and of with these and from various mouse as for for and for for The on and the of the was The was with cloning with and with the for the of and of the The cloning of these was with of the cDNA mouse spleen cDNA according to the with a in the of was of The cDNA was by with and In cloning with more than individual to the of the Based on the mouse sPLA2 cDNA and for of the part of the human homolog human spleen cDNA as a two of with two pairs of in the The for for and for for with The was on and the of the base pairs was and The and of cDNA as human and spleen The chromosome localization of the human sPLA2 was the of was to according to the with and the PLA2 encoding The was at for 2 and by for for and for for with and the The by and by The of the in of the was the was on the at the for and for of the of the mouse for the human sPLA2 and have a and sequence are with the The sPLA2 cDNA was by from mouse human spleen cDNA by with and and into to mouse and human sPLA2 expression of was into COS-7 in with At after culture The and disrupted by in of pH 2 mm and and at the The expression sPLA2 cDNA was also into COS-7 for the of and sPLA2 assays as S. Y. K. J. H. Yamamoto M. K. 1997; PubMed Scopus Google Scholar). sPLA2 assays at in a of of mm pH mm and of and to the of the of culture novel sPLA2 was for to the PLA2 in the of novel sPLA2 was in and to the The pH of sPLA2 activity was in the of mm at pH mm at pH mm at pH with human and by the culture of the cell the was by the sPLA2 activity was with and to individual with types of phospholipid as the The activity was of mm of substrate and mm in a of The and mm pH The fatty acids according to the of H. T. M. J. Res. Full Text PDF PubMed Google Scholar). and to the of of human sPLA2 of human group IIA sPLA2 was for The expressed as the of hydrolyzed phospholipids The of the novel sPLA2 cDNA was by and with blot was hybridized with the in mm mm pH W. Sci. S. A. PubMed Scopus Google (2.0 at and to human group IIA sPLA2 was by and for the of the The of the transcripts are from the molecular was into at a of In mice, was RNA was from several at after and to of mouse novel sPLA2 group IIA The of the was with and the In for novel sPLA2s in the we identified a cDNA number by residues of sPLA2s as a cDNA was sequence cloned from thymus of mouse of the group IIA sPLA2-deficient M. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, P. J. Vadas P. Pruzanski W. M. C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and a of functional sPLA2s We the cDNA to sequence from RNA from various mouse including the spleen, and cDNA as a expression was by of from mice, two transcripts and kb) expressed most in the spleen the the spleen cDNA as a the and the and to one that a functional The cDNA was cloned with the and by from spleen cDNA to the of the and its The cDNA identified a novel sPLA2 of amino its human we to the of the cDNA by from the mouse sPLA2 sequence under the that the and residues are the two for the human after several of one of the cDNA was to have a sequence to that of the of the mouse sPLA2 cDNA and amino acid residues with a of sequence we to the cDNA from a human spleen cDNA with the of cDNA The human sPLA2 cDNA consists of with one encoding amino The has sequence identity with the mouse the chromosome localization of the human novel sPLA2 we The two under a from human as well as from the sPLA2 that the gene sequence is by of the was of from of the The the sPLA2 gene location to chromosome 1p36.12 at to the sequence acid of novel mouse and human sPLA2s are in with of other sPLA2s. group and sPLA2 on group sPLA2 and human group sPLA2 H. and K. The sequence and that the and residues are from the of the and of amino acids the of the mature sPLA2 have a The molecular of mouse and human novel sPLA2s are and is one in and in the novel sPLA2s have identity with other and with group IIA sPLA2 and in mouse and of the sPLA2s cysteine residues to intramolecular disulfide by is characterized (15Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). In the mature of the novel mouse and human enzymes of cysteine with the cysteine residues in the sPLA2 the novel sPLA2 is of group IIA have the and are of group and IIC In novel sPLA2 has amino acid is in group IIA, IIC, and the a of the group the novel sPLA2 is most similar to group IIA sPLA2 and should be categorized into group on the by J. Biol. Chem. Full Text PDF PubMed Google Scholar). The sequence the molecular identity of novel sPLA2 from the PLA2s cloned (groups (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 14Dennis E.A. Trends Biol. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (758) Google we to the of the novel sPLA2 as group IID identified sPLA2s. J. R. N. Res. PubMed Scopus Google identified PLA2 activity in human and its amino The novel sPLA2 is distinct from the PLA2 in its The amino acid from mouse and human novel of the amino acids that are in functional sPLA2s including and to should be after from the the mouse and human novel sPLA2 into the expression and into COS-7 in 2 was in the of the culture of mouse and human sPLA2 cells, with the of the PLA2 activity was in the that novel sPLA2s from COS-7 human as a host in 2 sPLA2 activity was on Ca2+ and 2 mm Ca2+ for the sPLA2 was active a broad of pH 2 the activity of human group IIA sPLA2 was pH and at pH The Ca2+ and pH with features of sPLA2s (15Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). The substrate of novel human sPLA2 was with types of phospholipids that acid at the and have different fatty acids at the sn-2 as well as polar head human sPLA2 was by from the culture of that expressed the The of the the of the for the of specificity is also for the human group IIA sPLA2 is a of the sPLA2 family (3Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google and is a to the arachidonoyl-specific cytosolic Among the phospholipids was most efficiently The activity was substrate was When novel and more efficiently than and are hydrolyzed in In group IIA sPLA2 to the other phospholipids as T. H. S. H. M. J. Biol. Chem. Full Text PDF PubMed Google specificity of novel human sPLA2 fatty IIA activity of the novel and group IIA human sPLA2 was as under The expressed as the of hydrolyzed phospholipids of in a activity of the novel and group IIA human sPLA2 was as under The expressed as the of hydrolyzed phospholipids of The expression of the novel sPLA2 was by several human with in human novel expressed in the and spleen and in the thymus, and of mRNA (2.0 and 1.0 kb) and the these two transcripts are to the of a different of of the of we the structure of The of the of novel with that of group IIA is expressed in the and The expression of the novel sPLA2 in the spleen and thymus its in the of the and expression levels in rats and also examined. In one kb) of novel sPLA2 was in the spleen, thymus, and At after the expression of the sPLA2 mRNA was elevated in the thymus after with the the was in the spleen and in the In the of group IIA a was in the thymus and in to a in the The of group IIA sPLA2 mRNA after treatment was also in the and the of novel sPLA2 was In group IIA sPLA2-deficient mice, two transcripts (2.0 and 1.0 kb) in the spleen and thymus with the expression of sPLA2 mRNA was elevated in the thymus with of group IIA sPLA2 of from has to of a number of that been Among the PLA2 group sPLA2 and a novel of the cytosolic PLA2 of these (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 13Underwood K.W. Song C. Kriz R.E. Chang X.J. Knopf J.L. Lin L.-L. J. Biol. Chem. 1998; 273: 21926-21932Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). The of the sequence in the report is as the protein sequence by cDNA to be similar to is distinct from the group IIA of we cloned its cDNA and identified the novel sPLA2 from mouse and The novel biochemical to the sPLA2 in of molecular of sequence and of cysteine the requirement of Ca2+ as well as pH for catalysis, and the localization of the the cloned sPLA2 is the of the sPLA2 family in and the in as a functional because group IIC PLA2 is thought to be a in (15Tischfield J.A. J. Biol. Chem. 1997; 272: 17247-17250Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). the novel sPLA2 is most similar to the group IIA respect to the number and positions of cysteine residues as well as overall we to the novel sPLA2 as group IID identified IIA to IIC sPLA2s. The group IIA sPLA2 is thought to be one of the key enzymes for the pathogenesis of inflammatory diseases, because its expression is under various inflammatory R.M. T.J. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, T. H. H. PubMed Scopus Google Scholar, J. Nakano T. H. H. Res. PubMed Scopus Google Scholar, M. Inoue K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The to the novel mouse sPLA2 has been cloned from the in the group IIA PLA2 gene was naturally these are similar to group IIA mouse in their inflammatory PubMed Scopus Google Scholar, J.M. A. C.S. J. Google the novel sPLA2 a role for several of the group IIA In the in the expression of novel sPLA2 was in the spleen and thymus, is a expression similar to that of group sPLA2 in (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). the of producing sPLA2 is at present, the its role in to the endotoxin the expression of a novel sPLA2 was elevated in the thymus along with the group IIA sPLA2 expression of the novel sPLA2 in the thymus was also in for group IIA the progression of sepsis, is Lin J. 1994; Google Scholar). several of PLA2 in L.K. Res. PubMed Scopus Google Scholar, L.K. 1994; PubMed Scopus Google the novel sPLA2 a role in process. The expression of novel sPLA2 mRNA was also in after its was different from the of group IIA In the of the of novel sPLA2 to that of group IIA sPLA2 suggesting distinct for these two sPLA2s in the physiological and In to diverse expression we a group IIA and novel sPLA2s in to one of the S. Yamada M. K. T. Y. Y. T. M. T. M. Y. Yamada K. T. M. J. 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In the activity of the novel sPLA2 should be in the the location of a human novel sPLA2 gene on chromosome in the of group IIA, IIC, and V have already been mapped J.A. D.M. J. Engle S.J. Seilhamer J.J. G. A. 1996; PubMed Scopus Google group and sPLA2 are on chromosome and (12Cupillard L. Koumanov K. Mattei M.-G. Lazdunski M. Lambeau G. J. Biol. Chem. 1997; 272: 15745-15752Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 1994; PubMed Scopus Google Scholar). that sPLA2 V, and the novel and one a gene that is to have from gene mammalian such as and are to a gene that also R. Miller H. Biol. Google Scholar, M. S. L. J. Lipid Res. Full Text PDF PubMed Google Scholar). It is to that of the family in the structural of their Sci. 1991; Scholar). sPLA2 the that are under similar is the similar of expression the novel sPLA2 and the group IIA sPLA2 in the thymus in the to In the of human and group IIA sPLA2 a that is in several acute was identified R.M. T.J. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). T. H. and H. of the of the novel sPLA2 gene should a to the functional of In we novel mouse and human sPLA2s and characterized the and sPLA2 structural and features with sPLA2 and is to group IIA are to the physiological of sPLA2 and to its role in in inflammatory conditions. the of novel sPLA2 should more of distinct of and should also of the biochemical of the We for a of human group IIA We are to Nakano and for and to for the