Hyaluronan Endocytosis: Mechanisms of Uptake and Biological Functions

Hyaluronan (HA) is a non-sulfated linear glycosaminoglycan composed of multiple copies of the disaccharide unit of D-glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc); [β-1,4-GlcA-β -1,3-GlcNAc-]n where n is the number of repeating disaccharide subunits. HA is synthesized by the HA synthase family of enzymes. Three HA synthases, termed HAS1 through HAS3, have been identified in humans and in mice. These enzymes differ from each other in their catalytic activities (HAS3 > HAS2 > HAS1) as well as in the sizes of their final products. HAS1 and HAS2 polymerize long stretches of GlcA-GlcNAc disaccharide chains, whereas HAS3 polymerizes relatively short stretches (<300 kDa). Biosynthesis of HA is regulated by exogenous stimuli. For example, HA synthesis in fibroblasts is upregulated by phorbol esters, tumor growth factor alpha, and platelet derived growth factor, whereas HA synthesis in keratinocytes is upregulated by retinoic acid, epidermal growth factor, and tumor growth factor alpha and suppressed by corticosteroids [1-4]. HA is unique among extracellular matrix components in that it is not synthesized within the cell and transported to the surface via vesicles. Hyaluronan synthase is an integral membrane protein on the surface of cells. It links together UDP-α-Nacetyl-D-glucosamine and UDP-α-D-glucuronate to spin out long strands of HA. Because, unlike other extracellular matrix carbohydrates, HA is spooled out from the cell surface, it can achieve molecular weights ranging from five thousand Daltons to twenty million Daltons.