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  3. 6-Phosphogluconate Dehydrogenase Links Cytosolic Carbohydrate Metabolism to Protein Secretion via Modulation of Glutathione Levels

6-Phosphogluconate Dehydrogenase Links Cytosolic Carbohydrate Metabolism to Protein Secretion via Modulation of Glutathione Levels

  • Cell Chem Biol. 2019 Sep 19;26(9):1306-1314.e5. doi: 10.1016/j.chembiol.2019.05.006.
Haoxin Li 1,  Maria Ericsson 2,  Bokang Rabasha 3,  Bogdan Budnik 4,  Sze Ham Chan 5,  Elizaveta Freinkman 5,  Caroline A Lewis 5,  John G Doench 3,  Bridget K Wagner 3,  Levi A Garraway 3,  Stuart L Schreiber 6
Affiliations

Affiliations

  • 1 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: haoxinli6@gmail.com.
  • 2 Electron Microscope Facility, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 4 Mass Spectrometry and Proteomics Laboratory, Harvard University, Cambridge, MA 02138, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 6 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: stuart_schreiber@harvard.edu.
PMID: 31204288 DOI: 10.1016/j.chembiol.2019.05.006
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.

Keywords

6-phosphogluconate dehydrogenase; ECM; ER dilation; PGD; cancer; endoplasmic reticulum; extracellular matrix; glutathione; protein misfolding; protein secretion.

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