New molecules indispensable for hyaluronan degradation, HYBID (CEMIP/KIAA1199) and TMEM2 (CEMIP2): Differential roles in physiological and pathological non-neoplastic conditions

Abstract

The biological activity of hyaluronan (HA), a major component of the extracellular matrix in vertebrate tissues, depends on its molecular weight, and thus its degradation is a critical process for HA biological functions. Here, we review the characteristics of newly discovered proteins essential for HA degradation, hyaluronan-binding protein involved in hyaluronan depolymerization (HYBID), also known as cell migration inducing hyaluronidase 1 (CEMIP) and KIAA1199, and transmembrane protein-2 (TMEM2; alias CEMIP2). Human and mouse forms of HYBID exert their HA-degrading activity in special microenvironments including recycling endosomes. Mouse TMEM2 functions as a cell-surface hyaluronidase for HA turnover in local tissues, lymph nodes, and the liver. In contrast, the role of human TMEM2 in HA degradation is the subject of much debate. HYBID expression is upregulated by proinflammatory factors such as histamine and interleukin-6 and downregulated by transforming growth factor-β. HYBID is involved in physiological HA turnover in human skin and joint tissues and plays an important role in their pathological destruction by accelerating HA degradation.

Hypothesis of hyaluronan (HA) degradation mediated by HYBID and TMEM2 in mice and humans.HA degradation is carried out in two steps: The first step in local tissues and the second step in the lymphatic system and the liver. High molecular weight (HMW)-HA interacted with other extracellular matrix molecules such as proteoglycans is depolymerized into medium molecular weight (MMW)-HA fragments by mTMEM2 and mHYBID in mouse local tissues and by hHYBID and secreted hHYAL1 in human local tissues. In the second step, MMW-HA released from the local tissues flow into lymphatic vessels and regional lymph nodes, in which lymphatic endothelial cells are responsible for the degradation of MMW-HA into low molecular weight (LMW)-HA and oligosaccharides by mTMEM2, mHYAL1 and lysosomal glycosidases in mice and by hHYAL1 and lysosomal glycosidases in humans. HA fragments generated in the lymphatic system reach the general circulation and are further catabolized into monosaccharides by sinusoidal endothelial cells in the liver probably by following the similar pathways shown in the lymphatic system.