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(Sphingolipid Activator Proteins) in Lysosomal Storage And Proc. Nati. Acad. Sci. USA Vol. 87, pp. 3493-3497, May 1990 Medical Sciences Distribution of saposin proteins (sphingolipid activator proteins) in lysosomal storage and other diseases (Tay-Sachs disease/Sandhoff disease/fucosidosis/Gaucher disease/Niemann-Pick disease) SATOSHI MORIMOTO*, YOSHIMI YAMAMOTOt, JOHN S. O'BRIENt, AND YASUO KISHIMOTO Department of Neurosciences and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093 Communicated by Morris E. Friedkin, January 22, 1990 (receivedfor review November 27, 1989) ABSTRACT Saposins (A, B, C, and D) are small glycopro- was analyzed. Studies of the proteolytic processing of sa- teins required for the hydrolysis of sphingolipids by specific posins B and C showed that both are initially biosynthesized lysosomal hydrolases. Concentrations ofthese saposins in brain, as a large molecular mass precursor (70 kDa) that, after liver, and spleen from normal humans as well as patients with proteolytic processing, generates the 12-kDa saposin pro- lysosomal storage disease were determined. A quantitative teins (14, 15). This laboratory cloned a cDNA for saposins B HPLC method was used for saposin A, C, and D and a and C and showed that a common precursor generates both stimulation assay was used for saposin B. In normal tissues, polypeptides (16). O'Brien et al. (16) and Collard et al. (17) saposin D was the most abundant of the four saposins. Massive proposed that two additional activator proteins similar in accumulations of saposins, especially saposin A (about 80-fold structure to saposins B and C are generated by proteolysis of increase over normal), were found in brain of patients with the same precursor, which we call prosaposin. Tay-Sachs disease or infantile Sandhoff disease. In spleen of Furst et al. (18) obtained protein sequencing data on a adult patients with Gaucher disease, saposin A and D accumu- polypeptide that they isolated. After comparison with nucle- lations (60- and 17-fold, respectively, over normal) were higher otide sequences (16), they came to the conclusion that a than that of saposin C (about 16-fold over normal). Similar common precursor gives rise to three activator proteins, massive accumulations of saposins A and D were found in liver saposins B and C and the third protein that they isolated and of patients with fucosidosis (about 70- and 20-fold, respectively, called component C located within the carboxyl-terminal over normal). Saposin D was the primary sapoin stored in the portion of the precursor; they did not identify saposin A. liver ofa patient with Niemann-Pick disease (about 30-fold over We isolated saposin D from the spleen of a patient with normal). Moderate increases ofsaposins B and D were found in Gaucher disease, purified it to homogeneity, determined that a patient with GM1 gangiosidosis. Normal or near normal levels it had the same amino acid sequence as component C, and of all saposins were found in patients with Krabbe disease, demonstrated that it was a specific activator of sphingomy- metachromatic leukodystrophy, Fabry disease, adrenoleukod- elinase (19). Similar to saposin C, saposin D appears to exert ystrophy, I-cell disease, mucopolysaccharidosis types 2 and 3B, its effect upon the enzyme and did not bind sphingomyelin. or Jansky-Bielschowsky disease. The implications ofthe storage We also isolated the fourth potential saposin, called saposin of saposins in these diseases are discussed. A, from the spleen ofa patient with Gaucher disease, purified it to homogeneity, and demonstrated that saposin A, like Sphingolipid activator proteins are small glycoproteins re- saposin C, is a specific activator of 3-glucosylceramidase and quired for the maximal hydrolysis ofsphingolipids by specific galactosylceramide,3-galactosidase (20). Saposin A, like sa- lysosomal hydrolases. Sphingolipid activator protein 1 dis- posins C and D, activates by binding to these enzymes not to covered in 1964 (1) (herein termed saposin B) activates the lipid substrates. Presented in Fig. 1 is the nomenclature we hydrolysis of cerebroside sulfate, GM1 ganglioside, and proposed for this family of proteins (Fig. 1). globotriaosylceramide by arylsulfatase A, acid fl-galacto- Jnui and Wenger (21) reported that saposin B accumulated sidase, and a-galactosidase, respectively (2-5), and also in tissues of patients with lysosomal storage diseases, espe- appears to promote hydrolysis of a variety of other lipids cially tissue from patients with infantile GM1 gangliosidosis. including glycerolipids (6). A second activator protein, dis- The accumulation of saposin C in the spleen of patients with covered in 1971 (7), sphingolipid activator protein 2 (herein Gaucher disease has been known since its discovery (7). In termed saposin C) activates the hydrolysis of glucosylcera- the present report we describe the tissue distributions and mide and galactosylceramide by B-glucosylceramidase (EC concentrations of saposins A, B, C, and D in lysosomal 3.2.1.45) and galactosylceramide 3-galactosidase (EC storage and other diseases. Massive accumulations, espe- 3.2.1.46), respectively (8). Saposin C acts differently than cially of saposin A, were found in brain of patients with saposin B since it interacts with the above enzymes increas- Tay-Sachs disease or Sandhoff disease and in liver of pa- ing their maximal velocity and decreasing their Michaelis tients with fucosidosis and accumulations of saposin D were constant (9-11), whereas saposin B binds lipid substrates found in patients with Niemann-Pick disease. solubilizing them for hydrolysis. A third activator protein termed sphingolipid activator protein 3, also known as GM2 MATERIALS AND METHODS activator, is a specific activator for the hydrolysis of gangli- Human Tissues. Human tissues used in this study were oside GM2 by GM2 ,-N-acetylgalactosaminidase (12, 13). collected over many years and stored at -20°C in this labo- Sphingolipid activator protein 3 is genetically distinct and unrelated to the saposins studied here. ratory. Diagnoses were made by pathological examination, The two remaining saposin proteins, saposins A and D, analysis of storage material, and enzyme assays for the ap- were discovered (16) in 1989 after the cDNA encoding them *Present address: Faculty of Pharmaceutical Sciences, Kyushu, University, Fukuoka 812, Japan. The publication costs of this article were defrayed in part by page charge tPresent address: Department of Biology, Hamamatsu University, payment. This article must therefore be hereby marked "advertisement" School of Medicine, Hamamatsu. Shizuoka, 431-31, Japan. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 3493 Downloaded by guest on September 30, 2021 3494 Medical Sciences: Morimoto et al. Proc. Natl. Acad. Sci. USA 87 (1990) appeared after the saposin A peak on anion-exchange HPLC. Western blot of the peak after SDS/PAGE revealed that it is 1 60 143 195 275 311 390405 487 524 an unknown derivative of saposin A (data not shown). Saposins in Gaucher Disease. Saposin C was first isolated and found to accumulate in spleen from patients with adult Gaucher disease (7). Our investigation disclosed that this saposin is not the most abundant saposin accumulating. In 2 3 4 5 the four spleens examined total saposin ranged from 3267 to above FIG. 1. Nomenclature of saposin proteins. Prosaposin, the pre- 3652 tkg/g (dry weight), a 20- to 22-fold increase cursor of saposins A, B, C, and D, is shown as a bar with the positions normal; about one-half of the increase was due to saposin A, of the four saposins crosshatched. Locations of peptides are indi- which accumulated to levels averaging 60 times normal. cated by brackets. Brackets: 1, prosaposin (residues 1-524); 2, Saposin C was elevated 17 times normal, saposin D was 16 saposin A (residues 60-143); 3, saposin B (residues 195-275); 4, times normal, and saposin B was 5 times normal. Saposins saposin C (residues 311-390); 5, saposin D (residues 405-487). did not accumulate in the brain of two patients with infantile Gaucher disease. propriately deficient enzyme. Each disease listed is accompa- Saposins in GM1 Gangliosidosis. Saposin B has been shown nied by its appropriate number as assigned by McKusick (22). to accumulate in the liver of patients with infantile GM1 Determination of Saposin A, B, C, and D. Amounts of gangliosidosis (21). Our examination of liver from two such individual saposins were determined by a method to be patients showed that saposin D accumulated to nearly the described elsewhere. Individual human tissues (0.4-3.8 g) same extent as saposin B (about 8 times normal). In juvenile were homogenized in water and the homogenates were boiled GM1 gangliosidosis a smaller increase in saposin B was found and centrifuged. The concentrations of saposins A, C, and D in liver and a somewhat larger increase in saposins A and C in the supernatant were determined by two consecutive was found in brain. HPLC separations. The boiled extract was first fractionated Saposins in Fucosidosis. In patients with fucosidosis, mas- on a an acetonitrile gradient. C4 reversed-phase column with of saposins A and D were found in liver. After the impurities were eluted, saposins A, C, and D were sive accumulations at acetonitrile concentrations and this In one patient saposin A accumulated to levels 102 times eluted together high 23 normal. fraction was then analyzed by an anion-exchange HPLC normal whereas saposin D was about times using NaCl gradient. Saposins D, A, and C were eluted from Accumulations of saposins B and C were less significant (7- the column in individual peaks and quantitated by measuring to 17-fold increase). Accumulations of saposins in spleen and peak areas. Saposin B was quantified by determining its brain were modest. stimulative activity on pure human liver GM1 ganglioside In the brain from one fucosidosis patient, an extra peak (3-galactosidase. (retention time 11.6 min) was observed after anion-exchange HPLC.
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