MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect
Nataly Shtraizent,
Charles DeRossi,
Shikha Nayar,
Ravi Sachidanandam,
Liora S Katz,
Adam Prince,
Anna P Koh,
Adam Vincek,
Yoav Hadas,
Yujin Hoshida,
Donald K Scott,
Efrat Eliyahu,
Hudson H Freeze,
Kirsten C Sadler,
Jaime Chu
Affiliations
Nataly Shtraizent
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Shikha Nayar
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Ravi Sachidanandam
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
Liora S Katz
Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, United States
Adam Prince
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States
Anna P Koh
Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, United States
Adam Vincek
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
Yoav Hadas
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
Yujin Hoshida
Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, United States
Donald K Scott
Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, United States
Efrat Eliyahu
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
Hudson H Freeze
Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism.
