Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells This information is current as Svein O. Kolset and Gunnar Pejler of September 25, 2021. J Immunol 2011; 187:4927-4933; ; doi: 10.4049/jimmunol.1100806 http://www.jimmunol.org/content/187/10/4927 Downloaded from References This article cites 63 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/187/10/4927.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells Svein O. Kolset* and Gunnar Pejler† Among the different proteoglycans expressed by mam- where a compound denoted “macromolecular heparin” was mals,serglycinisinmostimmunecellsthedominatingspe- identified (2). Later, this type of compound was shown to be cies. A unique property of serglycin is its ability to adopt present also in rat peritoneal MCs (3, 4) and was subsequently highly divergent structures, because of glycosylation with classified as a proteoglycan (5). Moreover, it was shown that variable types of glycosaminoglycans when expressed by the proteoglycan was protease resistant and rich in Ser and different cell types. Recent studies of serglycin-deficient Gly residues (5). animals have revealed crucial functions for serglycin in a Among all proteoglycans, serglycin was the first to be diverse array of immunological processes. However, its identified at the cDNA level and was named so because of Downloaded from exact functionvariestoalargeextentdependingonthecel- a characteristic, extensive stretch of Ser-Gly repeats found in lular context of serglycin expression. Based on these find- the serglycin core protein of all species (6–10). The Ser resi- ings, serglycin is emerging as a structural and functional dues of these repeats constitute the GAG attachment sites. chameleon, with radically different properties depending Because of the close proximity of such sites, serglycin is on its exact cellular and immunological context. The densely substituted with GAG chains. Notably, this dense http://www.jimmunol.org/ Journal of Immunology, 2011, 187: 4927–4933. clustering of GAGs provides the basis for the strong protease resistance of serglycin (2–5, 11) and may also have additional functional implications, for example, to enable tight packag- roteoglycans are built up of a protein part, the so- ing of large amounts of GAG-binding compounds within a called core protein, which is glycosylated with sul- small volume. P fated and thereby negatively charged glycosamino- N-terminal sequencing of serglycin isolated from condi- glycans (GAGs). Proteoglycans can be roughly divided into tioned media of two different monocyte cell lines revealed cell surface-associated (e.g., syndecans, glypicans) and extra- extensive processing of the core protein N terminus (12, 13). cellular species (e.g., decorin, aggrecan, perlecan), but they However, it is not known whether the N-terminal processing by guest on September 25, 2021 can also be found within intracellular secretory compartments, of serglycin has any functional consequence. serglycin being the most notable example (1). 2 2 The type and extent of sulfation of GAG chains attached to The relatively recent generation of serglycin / mice has the serglycin core protein varies extensively between cell types revealed a wide impact of serglycin on the functional prop- (Fig. 1, Table I). The most well-known serglycin-associated erties of numerous immune cells. Intriguingly, though, the GAG is heparin, a GAG species with a remarkably high extent exact function of serglycin varies extensively between different serglycin-expressing cell types. A likely explanation for this is of sulfation, which is expressed only in connective tissue type its remarkably variable glycosylation pattern in different cells, MCs (Fig. 1, Table I). In several cells found in the circulation, ranging from glycosylation with highly sulfated GAGs of such as lymphocytes, platelets, and monocytes, serglycin is heparin type in connective tissue type mast cells (MCs) to substituted with lower sulfated chondroitin 4-sulfate (CS-4) low-sulfated chondroitin sulfate (CS) chains in, for example, chains (Fig. 1, Table I) (29). However, several hematopoietic T lymphocytes. Hence serglycin can be regarded as a struc- cells, including mucosal type MCs, bone marrow-derived MCs, tural and functional chameleon, being able to dynamically and activated monocytes and macrophages, express CS with and radically change its structural and functional character- a higher extent of sulfation (“oversulfated CS”), either of istics depending on biological context. CS-E or CS-diB type (Fig. 1, Table I) (30, 31). Notably, serglycin isolated from primary murine macrophages has Structural diversity of serglycin also been shown to contain heparan sulfate, a GAG type with The existence of a compound with the characteristics of ser- the same carbohydrate backbone structure as heparin but glycin was first indicated from studies on heparin in rat skin, having a lower sulfate content (Fig. 1, Table I) (26). Inter- *Department of Nutrition, University of Oslo, 0316 Oslo, Norway; and †Department Biochemistry, BMC, Box 575, 75123 Uppsala, Sweden (G.P.) or Department of Nu- of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, trition, University of Oslo, Box 1046, Blindern, 0316 Oslo, Norway (S.O.K.). E-mail 75123 Uppsala, Sweden addresses: [email protected] (G.P.) and [email protected] (S.O.K.) Received for publication June 8, 2011. Accepted for publication August 18, 2011. Abbreviations used in this article: CS, chondroitin sulfate; CS-4, chondroitin 4-sulfate; GAG, glycosaminoglycan; MC, mast cell; WT, wild type. This work was supported by Formas, the Swedish Research Council; King Gustaf V 80-Year Anniversary Fund; Torsten and Ragnar So¨derberg Foundation; the Swedish Cancer Founda- Ó tion; the Throne Holst Foundation; and South-Eastern Norway Regional Health Authority. Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 Address correspondence and reprint requests to Gunnar Pejler or Svein O. Kolset, Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100806 4928 BRIEF REVIEWS: SERGLYCIN FIGURE 1. Different serglycin GAG structures. Orange represents iduronic acid; green represents glu- curonic acid; blue represents N-ace- tylgalactosamine; gray represents N- acetylglucosamine. Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 estingly, the GAG repertoire of serglycin also includes hybrid metastatic carcinomas (28). With the use of an anti-serglycin proteoglycans, carrying both heparin and CS chains (32), Ab, the serglycin core protein has been detected in spleen, adding to its structural complexity. lymph nodes, and bone marrow (37–39). The size of serglycin may vary depending on the number Serglycin expression has been most thoroughly studied in of GAG chains attached to the protein core and because of MCs. An early study suggested that MCs have a high capacity variations in chain length of the attached GAGs (29). Of note, for serglycin expression as compared with other cell types an early study in eosinophils showed that the length of the (40). In agreement with this notion, serglycin is strongly in- serglycin CS-4/CS-E chains increased after stimulation with duced during the process of MC differentiation from bone IL-3 or GM-CSF (25), suggesting that serglycin may undergo marrow stem cells (41). Interestingly, the expression of sul- profound structural alterations in response to immunological fotransferases needed to synthesize CS-E was upregulated in signals. Most likely, such structural dynamics will influence tandem, whereas enzymes involved in heparin synthesis were the functional properties of serglycin with regard to storage expressed later in the differentiation process (41). Further- and/or release of bound compounds. As an example, Wistar– more, MC activation, leading to secretion of granule content Furth rats have a platelet phenotype with similarities to the (including serglycin), induced serglycin mRNA expression human gray platelet syndrome, proposed to be due to the and, again, expression of CS-E–related enzymes. In contrast, abnormally low size of the serglycin proteoglycans present in heparin-synthesizing enzymes were downregulated after acti- the a-granules (33). vation (41). These studies suggest dynamic regulation of serglycin expression and, in particular, differences in the re- Regulation of serglycin expression gulation of distinct sulfotransferases that