Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia

Eoin P. Cummins,Terence A. Agbor,Carsten C. Scholz,Katrina M. Comerford,Alex Cheong,Gerard Cagney,Ulrike Bruning,Ambrose Clarke,Cormac T. Taylor

doi:10.1074/jbc.m110.115931

Abstract

Under conditions of hypoxia, most eukaryotic cells undergo a shift in metabolic strategy, which involves increased flux through the glycolytic pathway. Although this is critical for bioenergetic homeostasis, the underlying mechanisms have remained incompletely understood. Here, we report that the induction of hypoxia-induced glycolysis is retained in cells when gene transcription or protein synthesis are inhibited suggesting the involvement of additional post-translational mechanisms. Post-translational protein modification by the small ubiquitin related modifier-1 (SUMO-1) is induced in hypoxia and mass spectrometric analysis using yeast cells expressing tap-tagged Smt3 (the yeast homolog of mammalian SUMO) revealed hypoxia-dependent modification of a number of key glycolytic enzymes. Overexpression of SUMO-1 in mammalian cancer cells resulted in increased hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion. Supporting this, non-transformed cells also demonstrated increased glucose uptake upon SUMO-1 overexpression. Conversely, cells overexpressing the de-SUMOylating enzyme SENP-2 failed to demonstrate hypoxia-induced glycolysis. SUMO-1 overexpressing cells demonstrated focal clustering of glycolytic enzymes in response to hypoxia leading us to hypothesize a role for SUMOylation in promoting spatial re-organization of the glycolytic pathway. In summary, we hypothesize that SUMO modification of key metabolic enzymes plays an important role in shifting cellular metabolic strategies toward increased flux through the glycolytic pathway during periods of hypoxic stress.

Highlights

A degree of hypoxia-induced glycolysis occurs even when new gene or protein synthesis is blocked. These data lead us to the hypothesis that post-translational mechanisms may play a role in the switch to increased glycolysis in hypoxia. One such post-translational modification that we have previously shown to be enhanced in hypoxic and ischemic conditions is by small ubiquitin related modifier-1 (SUMO-1) [2], leading us to the hypothesis that post-translational protein modification by members of the small ubiquitin related modifier (SUMO) family may contribute to the regulation of cellular metabolism during hypoxia
As the principal objective of increased glycolysis in hypoxia is increased anaerobic generation of ATP to support cell survival, we examined whether the increased glycolytic capacity of the SUMO-1 overexpressing cells is coupled to ATP generation
Because glycolysis alone generates a small net amount of ATP (2 molecules per molecule of glucose metabolized) without the requirement of oxygen, one metabolic option for cells is to enhance the rate of glycolysis such that this pathway becomes the primary source of cellular ATP generation, whereas actively decreasing oxidative phosphorylation

Summary

Introduction

Under conditions where oxygen demand exceeds supply (hypoxia), most cells retain the capacity to fundamentally shift metabolic strategy to a state where mitochondrial activity is decreased and glycolysis becomes the primary pathway for ATP generation [1]. This metabolic switch promotes cell survival during hypoxia and is adaptive in nature. Some cancer cells develop the ability to maintain enhanced glycolysis even when sufficient oxygen supply returns, a phenomenon known as the Warburg effect [35]. To date, the physiological implications for SUMO modification in hypoxia have remained largely unknown

Methods

Results

Conclusion