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

Accumulation of unfolded proteins within the endoplasmic reticulum (ER) of eukaryotic cells triggers the unfolded protein response (UPR), which activa tes transcription of several genes encoding ER chaperones and folding enzym es. This study reports that conversion of dolichol-linked Man(2)-(5)GlcNAc( 2) intermediates into mature Glc(3)Man(9)GlcNAc(2) oligosaccharides in prim ary human adult dermal fibroblasts is also stimulated by the UPR, This stim ulation was not evident in several immortal cell lines and did not require a cytoplasmic stress response. Inhibition of dolichol-linked Glc(3)Man(9)Gl cNAc(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 n ascent polypeptides. Glycosidic processing of asparagine-linked Glc(3)Man(9 )GlcNAc(2) in the ER leads to the production of monoglucosylated oligosacch arides that promote interaction with the lectin chaperones calreticulin and calnexin, Thus, control of the dolichol-linked Glc(3)Man(9)GlcNAc(2) suppl y gives the UPR the potential to maintain efficient protein folding in the ER without new synthesis of chaperones or folding enzymes.