Hyaluronan is a large glycosaminoglycan of extracellular matrix that provides a highly hydrated environment, favourable for actively growing and renewing cells and tissues. The high amount of hyaluronan in tissues is associated with organogenesis, wound healing, cancer progression and inflammation. Additionally, cell types responsible for secretion of anti-abrasive body fluids, like synovial and mesothelial cells have a high secretory capacity for hyaluronan. Hyaluronan synthesis is unique in several points of view: The hyaluronan synthases (HASs), acting on the plasma membrane, protrude the growing hyaluronan chain directly across plasma membrane into the extracellular space. Unlike other glycosaminoglycans, hyaluronan is not synthesized in the Golgi and does not have a core protein. GFP-techniques together with live cell confocal microscopy have enabled visualization of the intracellular localization and traffic of HASs. HAS transport to the plasma membrane is one of the latest regulatory points in hyaluronan synthesis. This is important, because HAS stays inactive until insertion to the plasma membrane, and inactive HASs are not retained on the plasma membrane. The insertion of HAS is suggested to be restricted at specific sites on the plasma membrane. This is related to the finding that the overexpression of HAS induces the growth of long, slender plasma membrane protrusions that are mechanically dependent on the newly synthesized hyaluronan on their surface. Cell types with naturally high hyaluronan production have similar microvilli-like protrusions that are surrounded by a thick layer of hyaluronan. Also the endogenous HASs are accumulated on similar cell protrusions, suggesting that they act as specific organelles for hyaluronan synthesis. Visualization of hyaluronan in live cells by a fluorescent, hyaluronan specific probe shows that each microvillus is surrounded by a 0.5-2.0 µm thick glycocalyx, produced by HAS on microvillus membrane, and responsible for the mechanical maintenance of the microvilli. Moreover, the hyaluronan coat is actually created and scaffolded by HAS-positive, actin-dependent microvilli. This secretory mechanism may be meaningful both for the creation of extracellular matrix as well as for secretion of viscous body fluids in vivo.
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