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. 2020 Dec 15;9:e63997. doi: 10.7554/eLife.63997

Figure 6. Model for IGF-1R engagement by the lectin chaperone cycle.

Figure 6.

In wild-type (WT) cells, N-glycans with three terminal glucoses are appended to IGF-1R. Trimming of two terminal glucoses by glucosidases I/II generates a monoglucosylated protein that supports an initial round of interaction with calreticulin (calnexin not shown, denoted by a 1). Trimming of the final glucose by glucosidase II yields a non-glucosylated N-glycan. If recognized as non-native primarily by UDP-glucose:glycoprotein glucosyltransferase (UGGT)1, and to a lesser extent UGGT2, IGF-1R may then be reglucosylated, supporting a second round of interaction with calreticulin (denoted by a 2+). Multiple rounds of trimming, reglucosylation, and binding to calnexin or calreticulin can occur until proper folding and trafficking. Under this system, IGF-1R is efficiently trafficked from the ER and mature IGF-1R accumulates. When glucosidase I/II activity is inhibited by treatment with deoxynojirimycin (DNJ) in WT cells, all rounds of binding to the lectin chaperones are ablated and IGF-1R is retained in the ER, yielding primarily pro IGF-1R. In UGGT1/2-/- cells, initial binding to calnexin or calreticulin directed by glucosidases I/II trimming is maintained but rebinding via reglucosylation does not occur. Under this system, IGF-1R is inefficiently trafficked from the ER. In ALG6-/- cells, N-glycans are transferred without glucoses, eliminating the initial round of binding to calnexin or calreticulin by glucosidases trimming. Only the second round of binding is supported by UGGT1, and to a lesser extend UGGT2, mediated reglucosylation. Upon treatment with DNJ, reglucosylated IGF-1R may persistently interact with the lectin chaperones resulting in ER retention.