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

• DOI: 10.1074/jbc.m110.115931
• Publication Date: 2010-12-02T01:37:58Z
• Authors: Terence A. Agbor; Alex Cheong; Katrina M. Comerford; Carsten C. Scholz; Ulrike Bruning; Ambrose Clarke; Eoin P. Cummins; Gerard Cagney; Cormac T. Taylor
• Keywords: Hypoxia; Anaerobic glycolysis; Bioenergetics; Metabolic pathway

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, underlying mechanisms have remained incompletely understood. Here, we report that induction hypoxia-induced glycolysis retained when gene transcription or protein synthesis are inhibited suggesting involvement additional post-translational mechanisms. Post-translational modification by small ubiquitin related modifier-1 (SUMO-1) induced hypoxia and mass spectrometric analysis using yeast expressing tap-tagged Smt3 (the homolog mammalian SUMO) revealed hypoxia-dependent number key enzymes. Overexpression SUMO-1 cancer resulted resistance to ATP depletion. Supporting this, non-transformed also demonstrated glucose uptake upon overexpression. Conversely, overexpressing de-SUMOylating enzyme SENP-2 failed demonstrate glycolysis. focal clustering enzymes response leading us hypothesize role SUMOylation promoting spatial re-organization In summary, SUMO plays an important shifting cellular strategies toward pathway during periods hypoxic stress. IntroductionIn steady state (when oxygen levels within cell exceed requirements), activity pathway, TCA (tricarboxyic acid) cycle electron transport chain combine generate ∼38 molecules adenosine triphosphate (ATP) per molecule metabolized. Glycolysis each 2 with remaining 34 being produced oxidative phosphorylation. This process provides necessary maintain physiologic function. However, under where demand exceeds supply (hypoxia), retain capacity fundamentally strategy mitochondrial decreased becomes primary generation (1Semenza G.L. Biochem. J. 2007; 405: 1-9Crossref PubMed Scopus (416) Google Scholar). Normally, switch promotes survival thus adaptive nature. such cases, back predominantly metabolism balance restored. phenomenon known as Pasteur effect (3Seagroves T.N. Ryan H.E. Lu H. Wouters B.G. Knapp M. Thibault P. Laderoute K. Johnson R.S. Mol. Cell. Biol. 2001; 21: 3436-3444Crossref (472) Alternatively, compartment growing tumor, has outgrown local blood supply, ability develop enhanced confers advantage tumor. Furthermore, some even sufficient returns, Warburg (35Racker E. Am. Sci. 1972; 60: 56-63PubMed Thus, increase rate implications both health disease. The molecular these switches function area intense investigation.One mechanism underpins transcriptional up-regulation hypoxia-inducible factor, HIF current study, provide data that, addition non-transcriptional involving facilitates rapid occurs hypoxia.The modifier (SUMO) 2The abbreviations used are: SUMO, ubiquitin-related modifier; MEF, mouse embryonic fibroblasts. family three proteins ∼17 kDa mammals one member Saccharomyces cerevisiae, modify wide range target (10Hay R.T. 2005; 18: 1-12Abstract Full Text PDF (1310) Scholar, 11Johnson E.S. Annu. Rev. 2004; 73: 355-382Crossref (1369) 27Geiss-Friedlander R. Melchior F. Nat. 8: 947-956Crossref (1333) S. homologue been shown be essential viability Recent work HIF-1α itself (12Agbor T.A. Taylor C.T. Soc. Trans. 2008; 36: 445-448Crossref (18) 15Shao Zhang F.P. Tian Anders Friberg Wang X. Sjöland Billig FEBS Lett. 569: 293-300Crossref (130) 16Bae S.H. Jeong J.W. Park J.A. Kim Bae M.K. Choi S.J. K.W. Biophys. Res. 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We yeast. cells, overexpression basal uptake. isopeptidase SENP2 reversed involved promotion favoring generation. compliments HIF-dependent pathways adaptation event may contribute survival.DISCUSSIONUnder conditions, method aerobic respiration combined activities cycle, 9Taylor 409: 19-26Crossref (221) Collectively, processes allow efficient completely When limited, must change their sustain alone generates net amount (2 metabolized) without requirement oxygen, option enhance source generation, whereas actively decreasing For occur, elevation required. One facilitated transporters, governed master regulator expression, HIF-1α-dependent alterations regulators favor decrease chain, respectively, stress (4Kim Tchernyshyov I. Semenza Dang C.V. 3: 177-185Abstract (2520) 5Papandreou Cairns R.A. Fontana L. Lim A.L. Denko N.C. 187-197Abstract (1579) 6Semenza Physiology. 24: 97-106Crossref (672) 7Iyer N.V. Kotch L.E. Agani Leung S.W. Laughner Wenger R.H. Gassmann Gearhart J.D. Lawler A.M. Yu A.Y. Genes Dev. 1998; 12: 149-162Crossref (2021) 8Fukuda Shimoda 129: 111-122Abstract (900) hypothesized events supported posttranslational facilitate challenged acute insult.Modification processes. alters profile SUMO-modified increases enzymes, accompanied enhancement hypothesis positively regulate promote absence oxygen. Three questions remain our understanding finding.First, what hypoxia-sensing proteins? functional importance sumoylation described, currently poorly A publication provided evidence inverse relationship between activation machinery (17Bossis 349-357Abstract (308) studies, it proposed sumoylation. thought due reactive species sensitivity desumoylating production proton leak, result leads subcellular microenvironment favorable enzymes.Second, question relates hypoxia. state, majority conjugated little free available (27Geiss-Friedlander two possibilities: first, de novo pool up-regulates expression An alternative explanation observation redistribution from substrates preferentially normoxia those support several recently reported changes other stresses including heat shock, electrophil 30Golebiowski Matic Tatham M.H. Cole Yin Nakamura Cox Barton G.J. Mann Hay Signal. 2: ra24Crossref (382) 31Wuerzberger-Davis S.M. Seufzer B.J. Miyamoto Oncogene. 26: 641-651Crossref (70) Scholar), consistent "preferential redistribution" hypothesis.A third how overall activity. possibility here directly How remains unknown. conformation influence its case ubiquitination deiodinase results reversible deactivation (29Sagar G.D. Gereben B. Callebaut Mornon J.P. Zeöld da Silva W.S. Luongo Dentice Tente Freitas B.C. Harney Zavacki Bianco A.C. 4774-4783Crossref (83) Whether GAPDH unknown.Alternatively rearrangement SUMO-1-modified cytoplasm into discreet complexes substrate channeling enhancing efficiency relative determined but human protozoan parasites, trypanosomes (34Michels P.A. Bringaud Herman Hannaert V. Biochim. Acta. 1763: 1463-1477Crossref (245) interaction SUMO-1, E3 ligase PIAS3, rate-limiting enzyme, pyruvate kinase (36Spoden G.A. Morandell Ehehalt Fiedler Jansen-Dürr Hermann Zwerschke 107: 293-302Crossref (61) any effects on yet investigated.Finally, significance clearly elucidated. propose hypoxic/ischemic ischemia. Tumor hand exploit same survive maladaptive mechanism. conjugation implicated Several reports components different cancers prostate thyroid adenomas exist (32Jacques Baris O. Prunier-Mirebeau Savagner Rodien Rohmer Franc Guyetant Malthiery Reynier Clin. Endocrinol. 90: 2314-2320Crossref (98) 33Cheng Bawa T. Lee Gong Neoplasia. 667-676Crossref (182) leukemic lines (HL60 HL60RV) abundant vincristine-resistant HL60RV line (39Vigodner Weisburg J.H. Shrivastava Marmor Fathy Skop N. Tissue 336: 277-286Crossref (4) Taken together tumors survival. associated indicating mediating fundamental observed encounters microenvironment.