Mast Cell Differentiation and Activation Is Closely Linked to Expression of Genes Coding for the Serglycin Proteoglycan Core Protein and a Distinct Set of Chondroitin Sulfate and Heparin Sulfotransferases

Abstract

Serglycin (SG) proteoglycan consists of a small core protein to which glycosaminoglycans of chondroitin sulfate or heparin type are attached. SG is crucial for maintaining mast cell (MC) granule homeostasis through promoting the storage of various basic granule constituents, where the degree of chondroitin sulfate/heparin sulfation is essential for optimal SG functionality. However, the regulation of the SG core protein expression and of the various chondroitin sulfate/heparin sulfotransferases during MC differentiation and activation are poorly understood. Here we addressed these issues and show that expression of the SG core protein, chondroitin 4-sulfotransferase (C4ST)-1, and GalNAc(4S)-6-O-sulfotransferase (GalNAc4S6ST) are closely linked to MC maturation. In contrast, the expression of chondroitin 6-sulfotransferase correlated negatively with MC maturation. The expression of N-deacetylase/N-sulfotransferase (NDST)-2, a key enzyme in heparin synthesis, also correlated strongly with MC maturation, whereas the expression of the NDST-1 isoform was approximately equal at all stages of maturation. MC activation by either calcium ionophore or IgE ligation caused an up-regulated expression of the SG core protein, C4ST-1, and GalNAc4S6ST, accompanied by increased secretion of chondroitin sulfate as shown by biosynthetic labeling experiments. In contrast, NDST-2 was down-regulated after MC activation, suggesting that MC activation modulates the nature of the glycosaminoglycan chains attached to the SG core protein. Taken together, these data show that MC maturation is associated with the expression of a distinct signature of genes involved in SG proteoglycan synthesis, and that MC activation modulates their expression.

Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells

“…An early study suggested that MCs have a high capacity for serglycin expression as compared with other cell types (40). In agreement with this notion, serglycin is strongly induced during the process of MC differentiation from bone marrow stem cells (41). Interestingly, the expression of sulfotransferases needed to synthesize CS-E was upregulated in tandem, whereas enzymes involved in heparin synthesis were expressed later in the differentiation process (41).…”

“…In agreement with this notion, serglycin is strongly induced during the process of MC differentiation from bone marrow stem cells (41). Interestingly, the expression of sulfotransferases needed to synthesize CS-E was upregulated in tandem, whereas enzymes involved in heparin synthesis were expressed later in the differentiation process (41). Furthermore, MC activation, leading to secretion of granule content (including serglycin), induced serglycin mRNA expression and, again, expression of CS-E-related enzymes.…”

“…Furthermore, MC activation, leading to secretion of granule content (including serglycin), induced serglycin mRNA expression and, again, expression of CS-E-related enzymes. In contrast, heparin-synthesizing enzymes were downregulated after activation (41). These studies suggest dynamic regulation of serglycin expression and, in particular, differences in the regulation of distinct sulfotransferases that most likely reflect a temporal regulation with importance for de novo synthesis of distinct granule components interacting with serglycin.…”

Molecular Interactions of Fullerene Derivatives in Human Serum and Inflammatory Cells

“…Inhibition of MC mediator release has been demonstrated with inhibitors of N-acetylglucosamine (20). In addition, IgE MC activation is closely linked to the function of serglycin proteoglycan core proteins; building blocks for the glycosaminoglycans (21). Thus, it is likely that TGA could prevent MC mediator release through its interactions with N-acetylglucosamine, which could disrupt the signaling pathway induced by FcεRI.…”

Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

“…The core protein containing 158 amino acid residues can be divided into 3 domains: a signal peptide domain, an N-terminal domain with unknown function, and a C-terminal domain (9). The functions of serglycin in various cells depend on the type and size of the GAG chains decorating the core protein (8,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”