Importance of N-glycosylation on CD147 for its biological functions

Abstract

Glycosylation of glycoproteins is one of many molecular changes that accompany malignant transformation. Post-translational modifications of proteins are closely associated with the adhesion, invasion, and metastasis of tumor cells. CD147, a tumor-associated antigen that is highly expressed on the cell surface of various tumors, is a potential target for cancer diagnosis and therapy. A significant biochemical property of CD147 is its high level of glycosylation. Studies on the structure and function of CD147 glycosylation provide valuable clues to the development of targeted therapies for cancer. Here, we review current understanding of the glycosylation characteristics of CD147 and the glycosyltransferases involved in the biosynthesis of CD147 N-glycans. Finally, we discuss proteins regulating CD147 glycosylation and the biological functions of CD147 glycosylation.

Figure 1.

Molecular model of the extracellular region of CD147 and its three glycosylation sites. The N-terminal domain is a typical C2 set immunoglobulin domain consisting of a β-barrel formed by the sheets EBA and GFCC′ and a conserved disulfide bond between strands B and F. The C-terminal domain is a typical I set immunoglobulin domain formed by the β-sheets DEBA and A′GFCC′ and a disulfide bond between Cys126 and Cys185 connecting strands B and F together. One N-linked glycosylation site, Asn44, lies at the end of strand B, i.e., the outermost position of the EBA sheet. The other two sites, Asn152 and Asn186, locate at the middle of C′D loop and strand F, respectively, with their lateral chains protruding oppositely from A′GFCC′ and DEBA sheets [42]. The figure is generated using the GlyProt software program [46,47] and we select oligomannoses on behalf of the potential diverse glycan structures to create the 3D protein structure of CD147.

Figure 2.

Intracellular biosynthesis and trafficking of glycosylated CD147. Immature high-mannose form of CD147 is modified in the ER, during which 1 glycans on the Asn152 are essential for quality control. Misfolded proteins without Asn152 glycosylation are degraded through ERAD pathway [53]; 2 A part of LG-CD147 then enter the Golgi while 3 the majority of newly produced LG-CD147 are degraded by the proteasome via the OS-9/SEL1L/Hrd1 pathway [54]. In the Golgi complex, LG-CD147 is further modified by many glycosyltransferases including GnT-III, GnT-IV, GnT-V and FuT-8 to form more complicated branching carbohydrate chains [53,55]. Subsequently, terminal modifications such as sialic acids are added to CD147 [56]; 4 Caveolin-1 binds to LG-CD147 in the Golgi, inhibits its maturation and escorts it into the cell membrane. LG-CD147 on the membrane fails to self-associate and induce MMPs [32]. However, it is also reported that caveolin-1 facilitates CD147 maturation [57]; 5 Then, HG-CD147 translocates to plasma membrane during which cyp60 in the Golgi is one of chaperones facilitating the translocation of CD147 [35]. Mature CD147 on the cell membrane form oligomers and a small fraction of transmembrane CD147 are shed and released into the extracellular matrix to act on neighbouring cells. Both forms of mature CD147 are capable of inducing MMPs; 6 MCT is one of ancillary proteins that accompany CD147 during its maturation in the ER and they form CD147-MCT complex on the membrane bearing the double roles of MMPs induction and lactic acid exportion [58,59].

Figure 3.

Potential glycan structures of CD147 and corresponding enzymes. In the medial-Golgi compartment, GnT-IV catalyzes β1–4 branch on complex N-Glycan structures, while GnT-III and GnT-V catalyze the formation of bisecting structure and β1–6 branch, respectively. The core fucose structure is catalyzed by FUT8. Then CD147 enters the trans-Golgi apparatus and receives sialic acid modification by sialyl transferase [53,55,56].