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. Author manuscript; available in PMC: 2016 Jan 1.
Published in final edited form as: Curr Protein Pept Sci. 2015;16(1):31–48. doi: 10.2174/1389203716666150213160438

Figure 2. Quality control of glycoprotein folding in the endoplasmic reticulum, ERAD and sorting in the secretory pathway.

Figure 2

The glycan G3M9 transferred to proteins during N-glycosylation is immediately trimmed by glucosidases GI and GII. Monoglucosylated species generated by GII may interact with lectin/chaperones CNX or CRT, thus facilitating folding, preventing aggregation and providing a mechanism for ER retention of misfolded species. A second cleavage by GII liberates glycoproteins from the CNX/CRT anchor. This is a check point in the secretory pathway: if the proteins have acquired their native conformation, they can continue to transit through the secretory pathway to their final destination. If not yet properly folded, UGGT adds a glucose unit to allow another round of interactions between misfolded glycoproteins and lectin/chaperones. GII is also responsible for the removal of the glucose added by UGGT. Cycles of deglucosylation and reglucosylation catalyzed by the opposing activities of UGGT and GII continue until the glycoproteins acquire their native tertiary structure, thereby allowing their transit to their final destination. Misfolded/slow-folding species are characterized by ER mannosidase(s) (ERManI/EDEM)-catalyzed N-glycan demannosylation. OS-9 recognizes Manα 1,6Man on the trimmed C arm and facilitates entry of misfolded glycoproteins into the ERAD pathway where the misfolded glycoproteins exit the ER and are degraded by the proteosome in the cytosol. A decrease in N-glycan mannose content significantly diminishes in vivo GII-mediated deglucosylation rates but does not affect in vivo UGGT-mediated glucosylation, thus increasing the possibility of displaying monoglucosylated structures able to interact with CNX/CRT for longer time periods, and providing one more chance to escape from ERAD. If the final destination of a glycoprotein is the lysosome (as for acidic hydrolases), a M6P tag is added by UDP-N-acetylglucosamine:lysosomal enzyme GlcNAc-1-phosphotranfserase (PT) and the N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (UCE) in the Golgi. M6P receptors (CD-MPR and CI-MPR) recognize this tag and concentrate these proteins in clatrin-coated vesicles that bud from trans Golgi network. MRH domain-containing proteins present in GIIβ subunit, OS-9, PT γ subunit and CD-MPR or CI-MPR are indicated.