Regulation of the dolichol pathway in human fibroblasts by the endoplasmic reticulum unfolded protein response

Accumulation of unfolded proteins within the endoplasmic reticulum (ER) of eukaryotic cells triggers the unfolded protein response (UPR), which activates transcription of several genes encoding ER chaperones and folding enzymes. This study reports that conversion of dolichol-linked Man(2)-(5)GlcNAc(2) intermediates into mature Glc(3)Man(9)GlcNAc(2) oligosaccharides in primary human adult dermal fibroblasts is also stimulated by the UPR, This stimulation was not evident in several immortal cell lines and did not require a cytoplasmic stress response. Inhibition of dolichol-linked Glc(3)Man(9)GlcNAc(2) synthesis by glucose deprivation could be counteracted by the UPR, improving the transfer of Glc(3)Man(9)GlcNAc(2) to asparagine residues on nascent polypeptides. Glycosidic processing of asparagine-linked Glc(3)Man(9)GlcNAc(2) in the ER leads to the production of monoglucosylated oligosaccharides that promote interaction with the lectin chaperones calreticulin and calnexin, Thus, control of the dolichol-linked Glc(3)Man(9)GlcNAc(2) supply gives the UPR the potential to maintain efficient protein folding in the ER without new synthesis of chaperones or folding enzymes.