Catalytic mechanisms, regulation, and anti-fibrotic roles of the TMEM2 cell surface hyaluronidase

About This Grant

PROJECT SUMMARY Hyaluronan (HA), a member of the glycosaminoglycan family, is one of the most abundant components of extracellular matrices. HA is a huge polysaccharide — a single linear HA polymer often exceeds 25,000 disaccharide units in length (~107 Da) and occupies the volume of a 300 nm diameter sphere. These unique biochemical and biophysical properties are accompanied by another unique biological feature of HA —an extremely rapid turnover. For instance, the metabolic half-life of HA in skin is only 1–1.5 days. This rapid turnover of HA emphasizes the particular importance of HA degradation in regulating systemic HA homeostasis and the biological effects of HA on cells. The prevailing model of HA catabolism stipulates that high-molecular weight HA in the extracellular space is first partially degraded into smaller HA fragments in the vicinity of the plasma membrane prior to internalization and ultimate degradation of the fragments in lysosomes. Accordingly, the existence of a hyaluronidase(s) that acts on the cell surface has been postulated. However, the identity of such a hyaluronidase(s) has long been elusive. In this context, we identified TMEM2, a previously uncharacterized transmembrane protein, as the sought-after cell surface hyaluronidase. Our subsequent studies have confirmed TMEM2's identity as a bona fide HA-degrading enzyme, and further demonstrated its functional significance in systemic HA catabolism, embryonic development, and cell adhesion and migration. Notably, the cellular and in vivo phenotypes caused by TMEM2 inactivation are much more striking than the phenotypes caused by inactivation of previously-known hyaluronidases. Moreover, an increasing number of genomic and transcriptomic studies implicate the TMEM2 gene in several human diseases. These observations indicate that mechanistic models of HA metabolism that do not incorporate TMEM2 are incomplete, and suggest that dysfunction of HA catabolism may have much more significant relevance to human diseases than previously thought. To fill this void in our understanding of the physiological and pathophysiological significance of HA catabolism, this project will comprehensively characterize the enzymology, three-dimensional structure, and cellular regulation of this novel hyaluronidase. Building on extensive published and preliminary data, we will determine the structural basis of TMEM2 catalytic function and elucidate cellular mechanisms that regulate TMEM2 function. The insights gained from this project are expected to uncover fundamental mechanisms governing HA metabolism and illuminate its pathophysiological significance in human disease.