Figure 6.

Model illustrating the relation between the trimming of N-linked sugar chains by ERManI, early glycoprotein trafficking events and ERAD in mammalian cells. After cleavage from the precursor oligosaccharide of two glucose residues by glucosidases I and II (GlcI-II), the newly synthesized glycoprotein binds to CNX or calreticulin (CRT). Trimming of mannose residues could occur in the ER lumen but inefficiently, given the low relative concentration of ERManI. The glycoprotein then moves to the ERQC where before or upon entry it is deglucosylated and CNX is released. It is then trimmed by the relatively high concentration of ERManI in the ERQC and recycles back to the peripheral ER where it is reglucosylated by the folding sensor UGGT to reassociate with CNX. These cycles are repeated until proper folding is achieved, and the glycoprotein is no longer a substrate of UGGT and exits to the Golgi or until a critical number of three mannose residues are excised (after which the glycoprotein cannot be reglucosylated), and the glycoprotein is delivered to ERAD, with the participation, through an undetermined mechanism, of EDEM1-3 and possibly of a putative mammalian orthologue of yeast YOS9.