Class I α-1,2 Mannosidases IB and IC: Subcellular Localization and Role in Mammalian Secretory Glycoprotein Quality Control

The Endoplasmic Reticulum is equipped with a quality control system that efficiently identifies irreversibly misfolded proteins and ensures their degradation in a process termed ER-associated degradation (ERAD). In mammalian cells, ERAD of a glycoprotein requires the removal of 3 or all 4 α-1,2 linked mannose residues from its N-glycan. The trimming is ascribed to ER α-1,2 mannosidase I (ERManI) and the EDEMs. Further cleavage of glycoproteins that exit the ER occurs by the action of α-1,2 mannosidases IA, IB, and IC (ManIA, B and C), previously reported to be in the Golgi. We have recently found that, surprisingly, ERManI and ManIA are not located in the ER or Golgi but normally reside in novel dynamic quality control vesicles (QCVs), only occasionally encountering their ER-located substrates. Remarkably, ManIA is also involved in glycoprotein folding quality control, acting in parallel with ERManI and the EDEMs. We have now re-evaluated the subcellular localization of ManIB and ManIC. Our recent results indicate that a certain population of these mannosidases colocalizes with Golgi and ERGIC markers, whereas a larger population appeared in a punctate pattern reminiscent of QCVs, similarly to ManIA and ERManI. As some misfolded glycoproteins can exit the ER to then be retrieved, quality control stages could also take place beyond the ER. In line with this, overexpression of ManIA, B and C accelerated ERAD of misfolded glycoproteins. Furthermore, knockdown of these mannosidases had an inhibiting effect on ERAD of these substrates, suggesting that they may indeed participate in glycoprotein quality control.