Rapid activation of glycogen phosphorylase by the endoplasmic reticulum unfolded protein response.
Endoplasmic reticulum (ER) stress is associated with misfolding of ER proteins and triggers the unfolded protein response (UPR). The UPR, in turn, helps restore normal ER function. Since fastidious N-linked glycosylation is critical for folding of most ER proteins, this study examined whether metabolic interconversions of precursors used for glycan assembly were controlled by the UPR. Thus, eight enzymes and factors with key roles in hexose phosphate metabolism were assayed in cytoplasmic extracts from primary dermal fibroblasts treated with UPR inducers. Stimulation of only one activity by the UPR was detected, AMP-independent glycogen phosphorylase (GP). GP activation required only 20 min of ER stress, with concurrent decreases in cellular glycogen and elevations of its metabolites Glc-1-P and Glc-6-P. Addition of phosphatase inhibitors to enzyme extracts from unstressed cells mimicked the effect of ER stress on GP activity, suggesting that phosphorylation of GP or a regulatory factor was involved. These data show that the UPR can modulate hexose metabolism in a manner beneficial for protein glycosylation. Since activation of GP appears to occur by a rapid post-translational process, it may be part of a general strategy of ER damage control, preceding the well-known transcription-dependent processes of the UPR that are manifested hours after the occurrence of ER stress.
Gill
Arvind
A
Department of Pharmacology, University of Texas-Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Gao
Ningguo
N
Lehrman
Mark A
MA
D000249:Adenosine Monophosphate / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry / Q000201:enzymology*; D020405:Dermis / Q000166:cytology; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006600:Hexosephosphates / Q000378:metabolism; D006801:Humans; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*; D017510:Protein Folding; D014415:Tunicamycin / Q000494:pharmacology
D006600:Hexosephosphates; D011134:Polysaccharides; D014415:Tunicamycin; D002110:Caffeine; D000249:Adenosine Monophosphate; D019298:Glucose-6-Phosphate; D006003:Glycogen; D024981:Glycogen Phosphorylase; D010744:Phosphoric Monoester Hydrolases; D004229:Dithiothreitol