Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells

In the endoplasmic reticulum (ER), N-glycans on glycoproteins play important roles in dictating the folding status of proteins by a sophisticated N-glycan-dependent protein quality control machinery. In this study we identified the dysregulation of ER-associated degradation (ERAD) in cells that were defective in the cytosolic deglycosylating enzyme, Ngly1. ERAD dysregulation was caused by an unexpected deglycosylating activity of endo-β-N-acetylglucosaminidase, another cytosolic deglycosylation enzyme, and this action resulted in the intracellular formation of protein aggregates. Our results clearly point to the critical role of N-glycans even in cytosolic events of the ERAD process by controlling the conformation/solubility of proteins. This study may also provide a potential mechanism for explaining the pathology of a human genetic disorder caused by mutations in the NGLY1 gene.