Advertisement

Hexosamine pathway regulates StarD7 expression in JEG-3 cells

  • Jésica Flores-Martín
  • Luciana Reyna
  • Mariano Cruz Del Puerto
  • María L. Rojas
  • Graciela M. Panzetta-Dutari
  • Susana Genti-Raimondi
Original Article
  • 28 Downloads

Abstract

StarD7 is a lipid binding protein involved in the delivery of phosphatidylcholine to the mitochondria whose promoter is activated by Wnt/β-catenin signaling. Although the majority of glucose enters glycolysis, ~ 2–5% of it can be metabolized via the hexosamine biosynthetic pathway (HBP). Considering that HBP has been implicated in the regulation of β-catenin we explored if changes in glucose levels modulate StarD7 expression by the HBP in trophoblast cells. We found an increase in StarD7 as well as in β-catenin expression following high-glucose (25 mM) treatment in JEG-3 cells; these effects were abolished in the presence of HBP inhibitors. Moreover, since HBP is able to promote unfolded protein response (UPR) the protein levels of GRP78, Ire1α, calnexin, p-eIF2α and total eIF2α as well as XBP1 mRNA was measured. Our results indicate that a diminution in glucose concentration leads to a decrease in StarD7 expression and an increase in the UPR markers: GRP78 and Ire1α. Conversely, an increase in glucose is associated to high StarD7 levels and low GRP78 expression, phospho-eIF2α and XBP1 splicing, although Ire1α remains high when cells are restored to high glucose. Taken together these findings indicate that glucose modulates StarD7 and β-catenin expression through the HBP associated to UPR, suggesting the existence of a link between UPR and HBP in trophoblast cells. This is the first study reporting the effects of glucose on StarD7 in trophoblast cells. These data highlight the importance to explore the role of StarD7 in placenta disorders related to nutrient availability.

Keywords

Hexosamine pathway StarD7 START domain JEG-3 cells UPR 

Abbreviations

AZA

O-Diazoacetyl-l-serine

DON

6-Diazo-5-oxo-l-norleucine

eIF2α

Eukaryotic translation initiation factor 2 subunit 1α

ER

Endoplasmic reticulum

FBS

Fetal bovine serum

GFAT

Glutamine fructose-6-phosphate amidotransferase

GlcNAc

N-acetylglucosamine

GRP78

Glucose regulated protein 78

HBP

Hexosamine biosynthetic pathway

IRE1α

Inositol-requiring enzyme 1

O-GlcNAc

O-GlcNAcylation

OGT

O-GlcNAc transferase

siRNA

Small interfering RNA

StarD7

StAR-related lipid transfer (START) domain containing 7

TBS

Tris buffered saline

UDP-GlcNAc

Uridine diphosphate N-acetylglucosamine

UPR

Unfolding protein response.

Notes

Acknowledgements

This work was funded by the Agencia Nacional de Promoción Ciencia y Técnica (FONCYT) PICT 2014-0806 and 2015-1781, and the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT-UNC). S.G-R. and G.M.P-D. are Career Investigators of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). J F-M, L-R, M-CDP and ML-R thank FONCYT and CONICET for her fellowships.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Efeyan A, Comb WC, Sabatini DM (2015) Nutrient-sensing mechanisms and pathways. Nature 517:302–310CrossRefGoogle Scholar
  2. 2.
    Denzel MS, Antebi A (2015) Hexosamine pathway and (ER) protein quality control. Curr Opin Cell Biol 33:14–18CrossRefGoogle Scholar
  3. 3.
    Hardiville S, Hart GW (2014) Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab 20:208–213CrossRefGoogle Scholar
  4. 4.
    Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022CrossRefGoogle Scholar
  5. 5.
    Taparra K, Tran PT, Zachara NE (2016) Hijacking the hexosamine biosynthetic pathway to promote EMT-mediated neoplastic phenotypes. Front Oncol 6:85CrossRefGoogle Scholar
  6. 6.
    Srinivasan V, Tatu U, Mohan V, Balasubramanyam M (2009) Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells. Mol Cell Biochem 328:217–224CrossRefGoogle Scholar
  7. 7.
    Sage AT, Walter LA, Shi Y, Khan MI, Kaneto H, Capretta A, Werstuck GH (2010) Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells. Am J Physiol Endocrinol Metab 298:E499–E451CrossRefGoogle Scholar
  8. 8.
    Lai E, Teodoro T, Volchuk A (2007) Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda) 22:193–201Google Scholar
  9. 9.
    Durand S, Angeletti S, Genti-Raimondi S (2004) GTT1/StarD7, a novel phosphatidylcholine transfer protein-like highly expressed in gestational trophoblastic tumour: cloning and characterization. Placenta 25:37–44CrossRefGoogle Scholar
  10. 10.
    Angeletti S, Rena V, Nores R, Fretes R, Panzetta-Dutari GM, Genti-Raimondi S (2008) Expression and localization of StarD7 in trophoblast cells. Placenta 29:396–404CrossRefGoogle Scholar
  11. 11.
    Angeletti S, Sanchez JM, Chamley LW, Genti-Raimondi S, Perillo MA (2011) StarD7 behaves as a fusogenic protein in model and cell membrane bilayers. Biochim Biophys Acta 1818:425–433CrossRefGoogle Scholar
  12. 12.
    Flores-Martin J, Rena V, Angeletti S, Panzetta-Dutari GM, Genti-Raimondi S (2013) The lipid transfer protein StarD7: structure, function, and regulation. Int J Mol Sci 14:6170–6186CrossRefGoogle Scholar
  13. 13.
    Horibata Y, Sugimoto H (2010) StarD7 mediates the intracellular trafficking of phosphatidylcholine to mitochondria. J Biol Chem 285:7358–7365CrossRefGoogle Scholar
  14. 14.
    Saita S, Tatsuta T, Lampe PA, Konig T, Ohba Y, Langer T (2018) PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria. EMBO J 37:e97909CrossRefGoogle Scholar
  15. 15.
    Bockelmann S, Mina JGM, Korneev S, Hassan DG, Muller D, Hilderink A, Vlieg HC, Raijmakers R, Heck AJR, Haberkant P, Holthuis JCM (2018) A search for ceramide binding proteins using bifunctional lipid analogs yields CERT-related protein StarD7. J Lipid Res 59:515–530CrossRefGoogle Scholar
  16. 16.
    Flores-Martin J, Rena V, Marquez S, Panzetta-Dutari GM, Genti-Raimondi S (2012) StarD7 knockdown modulates ABCG2 expression, cell migration, proliferation, and differentiation of human choriocarcinoma JEG-3 cells. PLoS ONE 7:e44152CrossRefGoogle Scholar
  17. 17.
    Flores-Martin J, Reyna L, Ridano ME, Panzetta-Dutari GM, Genti-Raimondi S (2016) Suppression of StarD7 promotes endoplasmic reticulum stress and induces ROS production. Free Radic Biol Med 99:286–295CrossRefGoogle Scholar
  18. 18.
    Horibata Y, Ando H, Zhang P, Vergnes L, Aoyama C, Itoh M, Reue K, Sugimoto H (2016) StarD7 protein deficiency adversely affects the phosphatidylcholine composition, respiratory activity, and cristae structure of mitochondria. J Biol Chem 291:24880–24891CrossRefGoogle Scholar
  19. 19.
    Yang L, Na CL, Luo S, Wu D, Hogan S, Huang T, Weaver TE (2017) The phosphatidylcholine transfer protein Stard7 is required for mitochondrial and epithelial cell homeostasis. Sci Rep 7:46416CrossRefGoogle Scholar
  20. 20.
    Yang L, Lewkowich I, Apsley K, Fritz JM, Wills-Karp M, Weaver TE (2015) Haploinsufficiency for Stard7 is associated with enhanced allergic responses in lung and skin. J Immunol 194:5635–5643CrossRefGoogle Scholar
  21. 21.
    Ha JR, Hao L, Venkateswaran G, Huang YH, Garcia E, Persad S (2014) beta-catenin is O-GlcNAc glycosylated at Serine 23: implications for beta-catenin’s subcellular localization and transactivator function. Exp Cell Res 321:153–166CrossRefGoogle Scholar
  22. 22.
    Olivier-Van Stichelen S, Dehennaut V, Buzy A, Zachayus JL, Guinez C, Mir AM, El Yazidi-Belkoura I, Copin MC, Boureme D, Loyaux D, Ferrara P, Lefebvre T (2014) O-GlcNAcylation stabilizes beta-catenin through direct competition with phosphorylation at threonine 41. FASEB J 28:3325–3338CrossRefGoogle Scholar
  23. 23.
    Olivier-Van Stichelen S, Guinez C, Mir AM, Perez-Cervera Y, Liu C, Michalski JC, Lefebvre T (2012) The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of beta-catenin and cell proliferation. Am J Physiol Endocrinol Metab 302:E417–E424CrossRefGoogle Scholar
  24. 24.
    Zhou F, Huo J, Liu Y, Liu H, Liu G, Chen Y, Chen B (2016) Elevated glucose levels impair the WNT/beta-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer. J Steroid Biochem Mol Biol 159:19–25CrossRefGoogle Scholar
  25. 25.
    Anagnostou SH, Shepherd PR (2008) Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines. Biochem J 416:211–218CrossRefGoogle Scholar
  26. 26.
    Rena V, Flores-Martín J, Angeletti S, Panzetta-Dutari G, Genti-Raimondi S (2011) StarD7 gene expression in trophoblast cells: contribution of SF-1 and Wnt-b-catenin signalling. Mol Endocrinol 8:1364–1375CrossRefGoogle Scholar
  27. 27.
    van Schadewijk A, van’t Wout EF, Stolk J, Hiemstra PS (2012) A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress. Cell Stress Chaperones 17:275–279CrossRefGoogle Scholar
  28. 28.
    Litvak V, Shaul YD, Shulewitz M, Amarilio R, Carmon S, Lev S (2002) Targeting of Nir2 to lipid droplets is regulated by a specific threonine residue within its PI-transfer domain. Curr Biol 12:1513–1518CrossRefGoogle Scholar
  29. 29.
    Ferrer CM, Sodi VL, Reginato MJ (2016) O-GlcNAcylation in cancer biology: linking metabolism and signaling. J Mol Biol 428:3282–3294CrossRefGoogle Scholar
  30. 30.
    Hanover JA, Krause MW, Love DC (2010) The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim Biophys Acta 1800:80–95CrossRefGoogle Scholar
  31. 31.
    Diaz P, Powell TL, Jansson T (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91:82CrossRefGoogle Scholar
  32. 32.
    Howerton CL, Bale TL (2014) Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. Proc Natl Acad Sci USA 111:9639–9644CrossRefGoogle Scholar
  33. 33.
    Howerton CL, Morgan CP, Fischer DB, Bale TL (2013) O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci USA 110:5169–5174CrossRefGoogle Scholar
  34. 34.
    Pantaleon M, Steane SE, McMahon K, Cuffe JSM, Moritz KM (2017) Placental O-GlcNAc-transferase expression and interactions with the glucocorticoid receptor are sex specific and regulated by maternal corticosterone exposure in mice. Sci Rep 7:2017CrossRefGoogle Scholar
  35. 35.
    Zhang Q, Na Q, Song W (2017) Moderate mammalian target of rapamycin inhibition induces autophagy in HTR8/SVneo cells via O-linked beta-N-acetylglucosamine signaling. J Obstet Gynaecol Res 43:1585–1596CrossRefGoogle Scholar
  36. 36.
    Sethi JK, Vidal-Puig AJ (2008) Wnt signalling at the crossroads of nutritional regulation. Biochem J 416:e11–e13CrossRefGoogle Scholar
  37. 37.
    Rena V, Angeletti S, Panzetta-Dutari G, Genti-Raimondi S (2009) Activation of beta-catenin signalling increases StarD7 gene expression in JEG-3 cells. Placenta 30:876–883CrossRefGoogle Scholar
  38. 38.
    Deng RP, He X, Guo SJ, Liu WF, Tao Y, Tao SC (2014) Global identification of O-GlcNAc transferase (OGT) interactors by a human proteome microarray and the construction of an OGT interactome. Proteomics 14:1020–1030CrossRefGoogle Scholar
  39. 39.
    Zachara NE, Hart GW (2004) O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim Biophys Acta 1673:13–28CrossRefGoogle Scholar
  40. 40.
    Sohn KC, Lee KY, Park JE, Do SI (2004) OGT functions as a catalytic chaperone under heat stress response: a unique defense role of OGT in hyperthermia. Biochem Biophys Res Commun 322:1045–1051CrossRefGoogle Scholar
  41. 41.
    Carvalho-Cruz P, Alisson-Silva F, Todeschini AR, Dias WB (2017) Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Dev Dyn 247:481–491CrossRefGoogle Scholar
  42. 42.
    Jang I, Kim HB, Seo H, Kim JY, Choi H, Yoo JS, Kim JW, Cho JW (2015) O-GlcNAcylation of eIF2alpha regulates the phospho-eIF2alpha-mediated ER stress response. Biochim Biophys Acta 1853:1860–1869CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Departamento de Bioquímica Clínica, Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCórdobaArgentina
  2. 2.Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)CórdobaArgentina
  3. 3.Departamento de Bioquímica Clínica, CIBICI-CONICET, Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCórdobaArgentina

Personalised recommendations