Regulation of TMEM2-mediated hyaluronan degradation by CD44 and LYVE-1

Hyaluronan (HA) is a major glycosaminoglycan of the extracellular matrix that regulates cell migration, signaling, and tissue homeostasis. Its turnover is controlled by coordinated synthesis by HA synthases and degradation by hyaluronidases. Among these hyaluronidases, TMEM2, the only known transmembrane hyaluronidase, plays a unique role in HA degradation at the cell surface. However, the cellular conditions that support its activity remain incompletely understood. To address this, researchers developed a cell-based HA turnover assay to examine TMEM2-mediated degradation of endogenously synthesized HA. Using this system, they show that TMEM2 readily degrades high-molecular weight HA synthesized by co-expressed HAS3. This degradation occurs only when TMEM2 and HAS3 are co-expressed in the same cells (cis), whereas co-culture of TMEM2-expressing cells with HAS3-expressing cells supports little or no degradation. Interestingly, HA-binding cell surface receptors CD44 and its homolog LYVE-1 promote efficient TMEM2-mediated HA degradation even under trans conditions, whereas other HA-binding proteins, including TSG-6, layilin, TLR2, RHAMM, and ICAM-1, do not. These findings suggest a spatially regulated mechanism of TMEM2 activity in which capture of HA at the cell surface, mediated by CD44 or LYVE-1, contributes to efficient HA degradation by TMEM2.