Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism

Figure 3 Proposed model for hyaluronan breakdown. Hyaluronan (HA) bound by a cell- or matrix-associated receptor such as CD44, HARE, or LYVE-1 is proposed to be hydrolyzed to intermediate-sized fragments by the GPI-linked HYAL2. The resulting fragments are then internalized by receptor-mediated endocytosis and transported to lysosomes. Once inside the lysosome, further degradation takes place through the action of the acid-active HYAL1. HYAL1 cleaves the intermediate-sized HA fragments to smaller fragments such that they become substrates for the sequential action of the exoglycosidases, β-glucuronidase (Gluc) and β-N-acetylhexosaminidase (Hex) which hydrolyze terminal GlcA and GlcNAc, respectively. The role of HYAL3 is unclear although its overexpression increases HYAL1 activity in cell culture based studies.