γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A

Mol Cell. 2019 Dec 19;76(6):857-871.e9. doi: 10.1016/j.molcel.2019.09.007. Epub 2019 Oct 2.

Abstract

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

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Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Proliferation
  • Enzyme Activation
  • Gluconates / metabolism*
  • Glucosephosphate Dehydrogenase / genetics
  • Glucosephosphate Dehydrogenase / metabolism
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • K562 Cells
  • MCF-7 Cells
  • Mice, Nude
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • PC-3 Cells
  • Pentose Phosphate Pathway
  • Protein Binding
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Ribulosephosphates / metabolism
  • Signal Transduction
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Tumor Burden
  • src-Family Kinases / metabolism

Substances

  • 6-phosphogluconolactone
  • Gluconates
  • Reactive Oxygen Species
  • Ribulosephosphates
  • ribulose 5-phosphate
  • Glucosephosphate Dehydrogenase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • STK11 protein, human
  • src-Family Kinases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Protein Phosphatase 2