MPI Depletion Enhances O-GlcNAcylation of P53 and Suppresses the Warburg Effect

Overview

Journal Elife

Specialty Biology

Date 2017 Jun 24

PMID 28644127

Citations 20

Authors

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

Soon will be listed here.

Abstract

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.

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