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Protein O-GlcNAcylation regulates Drosophila growth through the insulin signaling pathway

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Abstract

Modification of nuclear and cytosolic proteins by O-linked N-acetylglucosamine (O-GlcNAcylation) is ubiquitous in cells. The in vivo function of the protein O-GlcNAcylation, however, is not well understood. Here, we manipulated the cellular O-GlcNAcylation level in Drosophila and found that it promotes developmental growth by enhancing insulin signaling. This increase in growth is due mainly to cell growth and not to cell proliferation. Our data suggest that the increase in the insulin signaling activity is mediated, at least in part, through O-GlcNAcylation of Akt. These results indicate that O-GlcNAcylation is one of the crucial mechanisms involved in control of insulin signaling during Drosophila development.

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Abbreviations

GPX1:

Glutathione peroxidase 1

NButGT:

1,2-Dideoxy-2′-propyl-α-D-glucopyranoso-[2,1-D]-Δ2′-thiazoline

O-GlcNAc:

O-linked N-acetylglucosamine

OGT:

O-linked GlcNAc transferase

References

  1. Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022

    Article  PubMed  CAS  Google Scholar 

  2. Hanover JA, Forsythe ME, Hennessey PT, Brodigan TM, Love DC, Ashwell G, Krause M (2005) A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc Natl Acad Sci USA 102:11266–11271

    Article  PubMed  CAS  Google Scholar 

  3. Forsythe ME, Love DC, Lazarus BD, Kim EJ, Prinz WA, Ashwell G, Krause MW, Hanover JA (2006) Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc Natl Acad Sci USA 103:11952–11957

    Article  PubMed  CAS  Google Scholar 

  4. Shafi R, Iyer SP, Ellies LG, O’Donnell N, Marek KW, Chui D, Hart GW, Marth JD (2000) The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci USA 97:5735–5739

    Article  PubMed  CAS  Google Scholar 

  5. O’Donnell N, Zachara NE, Hart GW, Marth JD (2004) Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol 24:1680–1690

    Article  PubMed  Google Scholar 

  6. McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA (2002) Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci USA 99:10695–10699

    Article  PubMed  CAS  Google Scholar 

  7. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM (2008) Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451:964–969

    Article  PubMed  CAS  Google Scholar 

  8. Gandy JC, Rountree AE, Bijur GN (2006) Akt1 is dynamically modified with O-GlcNAc following treatments with PUGNAc and insulin-like growth factor-1. FEBS Lett 580:3051–3058

    Article  PubMed  CAS  Google Scholar 

  9. Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T (2008) O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett 582:829–834

    Article  PubMed  CAS  Google Scholar 

  10. Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW (2008) O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 314:2238–2248

    Article  PubMed  CAS  Google Scholar 

  11. Gambetta MC, Oktaba K, Muller J (2009) Essential role of the glycosyltransferase sxc/Ogt in Polycomb repression. Science 325:93–96

    Article  PubMed  CAS  Google Scholar 

  12. Sinclair DA, Syrzycka M, Macauley MS, Rastgardani T, Komljenovic I, Vocadlo DJ, Brock HW, Honda BM (2009) Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc Natl Acad Sci USA 106:13427–13432

    Article  PubMed  CAS  Google Scholar 

  13. Puig O, Marr MT, Ruhf ML, Tjian R (2003) Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17:2006–2020

    Article  PubMed  CAS  Google Scholar 

  14. Lee KS, Kwon OY, Lee JH, Kwon K, Min KJ, Jung SA, Kim AK, You KH, Tatar M, Yu K (2008) Drosophila short neuropeptide F signalling regulates growth by ERK-mediated insulin signalling. Nat Cell Biol 10:468–475

    Article  PubMed  CAS  Google Scholar 

  15. Kang JG, Park SY, Ji S, Jang I, Park S, Kim HS, Kim SM, Yook JI, Park YI, Roth J, Cho JW (2009) O-GlcNAc protein modification in cancer cells increases in response to glucose deprivation through glycogen degradation. J Biol Chem 284:34777–34784

    Article  PubMed  CAS  Google Scholar 

  16. Macauley MS, Whitworth GE, Debowski AW, Chin D, Vocadlo DJ (2005) O-GlcNAcase uses substrate-assisted catalysis: kinetic analysis and development of highly selective mechanism-inspired inhibitors. J Biol Chem 280:25313–25322

    Article  PubMed  CAS  Google Scholar 

  17. Marenda DR, Vrailas AD, Rodrigues AB, Cook S, Powers MA, Lorenzen JA, Perkins LA, Moses K (2006) MAP kinase subcellular localization controls both pattern and proliferation in the developing Drosophila wing. Development 133:43–51

    Article  PubMed  CAS  Google Scholar 

  18. Yu SY, Yoo SJ, Yang L, Zapata C, Srinivasan A, Hay BA, Baker NE (2002) A pathway of signals regulating effector and initiator caspases in the developing Drosophila eye. Development 129:3269–3278

    PubMed  CAS  Google Scholar 

  19. Struhl G, Basler K (1993) Organizing activity of wingless protein in Drosophila. Cell 72:527–540

    Article  PubMed  CAS  Google Scholar 

  20. Garofalo RS (2002) Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol Metab 13:156–162

    Article  PubMed  CAS  Google Scholar 

  21. Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE (2002) A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem 277:22115–22118

    Article  PubMed  CAS  Google Scholar 

  22. Park SY, Ryu J, Lee W (2005) O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Exp Mol Med 37:220–229

    PubMed  CAS  Google Scholar 

  23. Sekine O, Love DC, Rubenstein DS, Hanover JA (2010) Blocking O-GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J Biol Chem. doi:10.1074/jbc.M110.155192

  24. Verdu J, Buratovich MA, Wilder EL, Birnbaum MJ (1999) Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol 1:500–506

    Article  PubMed  CAS  Google Scholar 

  25. Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS, Cho JW (2006) Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol 8:1074–1083

    Article  PubMed  CAS  Google Scholar 

  26. Yang WH, Park SY, Ji S, Kang JG, Kim JE, Song H, Mook-Jung I, Choe KM, Cho JW (2010) O-GlcNAcylation regulates hyperglycemia-induced GPX1 activation. Biochem Biophys Res Commun 391:756–761

    Article  PubMed  CAS  Google Scholar 

  27. Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE (2004) Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GlcNAcase and HAT activities. J Biol Chem 279:53665–53673

    Article  PubMed  CAS  Google Scholar 

  28. Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H (1999) Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes 48:1562–1571

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank K. S. Cho, J. Chung, and K. Yu for fly stocks and DNA clones, and O. Puig and K. Yu for providing the anti-dFOXO antibody. We are also grateful to J. Lee and I. Jang for preliminary results on fly O-GlcNAcylation, other members of the Cho and Choe laboratories for helpful discussions, and E. Y. Kim and K. Yu for critical reading of the manuscript. This work was supported by the National Research Foundation (NRF) funded by the Korean Government (2010-0018923 to J.W.C. and 2010-0027736 to J.R.), World Class University Program (R31-2008-000-10086-0 to J.W.C. and J.R.) and Basic Research Program (2010-0008544 to K.-M.C.) through NRF of Korea funded by the Ministry of Education, Science and Technology and partly by KRF-2006-005-J04502 to J.W.C. Further partial support was received by NRF grant funded by the Korea government through the Center for Bioactive Molecular Hybrids (NO. R11-2003-019-00000-0 to K.S.K.). S.P. and S.-H.P are fellowship awardees of the Brain Korea 21 program. This work was made possible through the use of research facilities in the Yonsei Center for Biotechnology.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, 120-749, Korea

    Sujin Park, Jürgen Roth & Jin Won Cho

  2. Department of Biology, Yonsei University, Seoul, 120-749, Korea

    Si-Hyoung Park, Jin Won Cho & Kwang-Min Choe

  3. Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul, 120-749, Korea

    Ju Yuel Baek, Ye Jin Jy & Kwan Soo Kim

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  1. Sujin Park
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Correspondence to Jin Won Cho or Kwang-Min Choe.

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Park, S., Park, SH., Baek, J.Y. et al. Protein O-GlcNAcylation regulates Drosophila growth through the insulin signaling pathway. Cell. Mol. Life Sci. 68, 3377–3384 (2011). https://doi.org/10.1007/s00018-011-0640-7

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