1. 6-Phosphogluconate Dehydrogenase Links Cytosolic Carbohydrate Metabolism to Protein Secretion via Modulation of Glutathione Levels.
- Author
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Li H, Ericsson M, Rabasha B, Budnik B, Chan SH, Freinkman E, Lewis CA, Doench JG, Wagner BK, Garraway LA, and Schreiber SL
- Subjects
- Cell Line, Tumor, Cytosol metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress physiology, Extracellular Matrix metabolism, Humans, Phosphogluconate Dehydrogenase physiology, Protein Translocation Systems physiology, Carbohydrate Metabolism physiology, Glutathione metabolism, Phosphogluconate Dehydrogenase metabolism, Protein Translocation Systems metabolism
- Abstract
The proteinaceous extracellular matrix (ECM) is vital for the survival, proliferation, migration, and differentiation of many types of cancer. However, little is known regarding metabolic pathways required for ECM secretion. By using an unbiased computational approach, we searched for enzymes whose suppression may lead to disruptions in protein secretion. Here, we show that 6-phosphogluconate dehydrogenase (PGD), a cytosolic enzyme involved in carbohydrate metabolism, is required for ER structural integrity and protein secretion. Chemical inhibition or genetic suppression of PGD activity led to cell stress accompanied by significantly expanded ER volume and was rescued by compensating endogenous glutathione supplies. Our results also suggest that this characteristic ER-dilation phenotype may be a general marker indicating increased ECM protein congestion inside cells and decreased secretion. Thus, PGD serves as a link between cytosolic carbohydrate metabolism and protein secretion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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