Skip to main content

Advertisement

SpringerLink
Log in

Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Transthyretin (TTR) is a functional protein in the pancreatic β-cell. It promotes insulin release and protects against β-cell death. We now demonstrate by ligand blotting, adsorption to specific magnetic beads, and surface plasmon resonance that TTR binds to glucose-regulated proteins (Grps)78, 94, and 170, which are members of the endoplasmic reticulum chaperone family, but Grps78 and 94 have also been found at the plasma membrane. The effect of TTR on changes in cytoplasmic free Ca2+ concentration ([Ca2+]i) was abolished if the cells were treated with either dynasore, a specific inhibitor of dynamin GTPase that blocks clathrin-mediated endocytosis, or an antibody against Grp78, that prevents TTR from binding to Grp78. The conclusion is that TTR binds to Grp78 at the plasma membrane, is internalized into the β-cell via a clathrin-dependent pathway, and that this internalization is necessary for the effects of TTR on β-cell function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Blake CC (1981) Prealbumin and the thyroid hormone nuclear receptor. Proc R Soc Lond B Biol Sci 211:413–431

    Article  PubMed  CAS  Google Scholar 

  2. Jacobsson B, Carlström A, Platz A, Collins VP (1990) Transthyretin messenger ribonucleic acid expression in the pancreas and in endocrine tumors of the pancreas and gut. J Clin Endocrinol Metab 71:875–880

    Article  PubMed  CAS  Google Scholar 

  3. Itoh N, Hanafusa T, Miyagawa J, Tamura S, Inada M, Kawata S, Kono N, Tarui S (1992) Transthyretin (prealbumin) in the pancreas and sera of newly diagnosed type I (insulin-dependent) diabetic patients. J Clin Endocrinol Metab 74:1372–1377

    Article  PubMed  CAS  Google Scholar 

  4. Refai E, Dekki N, Yang SN, Imreh G, Cabrera O, Yu L, Yang G, Norgren S, Rossner SM, Inverardi L, Ricordi C, Olivecrona G, Andersson M, Jörnvall H, Berggren PO, Juntti-Berggren L (2005) Transthyretin constitutes a functional component in pancreatic beta-cell stimulus-secretion coupling. Proc Natl Acad Sci USA 102:17020–17025

    Article  PubMed  CAS  Google Scholar 

  5. Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, Uhles S, Yu L, Griffiths WJ, Zaitsev S, Leibiger I, Yang SN, Olivecrona G, Jörnvall H, Berggren PO (2004) Apolipoprotein CIII promotes Ca2+-dependent beta cell death in type 1 diabetes. Proc Natl Acad Sci USA 101:10090–10094

    Article  PubMed  CAS  Google Scholar 

  6. Divino CM, Schussler GC (1990) Receptor-mediated uptake and internalization of transthyretin. J Biol Chem 265:1425–1429

    PubMed  CAS  Google Scholar 

  7. Divino CM, Schussler GC (1990) Transthyretin receptors on human astrocytoma cells. J Clin Endocrinol Metab 71:1265–1268

    Article  PubMed  CAS  Google Scholar 

  8. Vieira AV, Sanders EJ, Schneider WJ (1995) Transport of serum transthyretin into chicken oocytes. A receptor-mediated mechanism. J Biol Chem 270:2952–2956

    CAS  Google Scholar 

  9. Kuchler-Bopp S, Dietrich JB, Zaepfel M, Delaunoy JP (2000) Receptor-mediated endocytosis of transthyretin by ependymoma cells. Brain Res 870:185–194

    Article  PubMed  CAS  Google Scholar 

  10. Sousa MM, Saraiva MJ (2001) Internalization of transthyretin. Evidence of a novel yet unidentified receptor-associated protein (RAP)-sensitive receptor. J Biol Chem 276:14420–14425

    PubMed  CAS  Google Scholar 

  11. Lernmark A (1974) The preparation of, and studies on, free cell suspensions from mouse pancreatic islets. Diabetologia 10:431–438

    Article  PubMed  CAS  Google Scholar 

  12. Hirschberg D, Tryggvason S, Gustafsson M, Bergman T, Swedenborg J, Hedin U, Jörnvall H (2004) Identification of endothelial proteins by MALDI-MS using a compact disc microfluidic system. Protein J 23:263–271

    Article  PubMed  CAS  Google Scholar 

  13. Hammond TG, Verroust PJ (1994) Trafficking of apical proteins into clathrin-coated vesicles isolated from rat renal cortex. Am J Physiol 266:554–562

    Google Scholar 

  14. Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10:839–850

    Article  PubMed  CAS  Google Scholar 

  15. Vieira AV, Schneider WJ (1993) Transport and uptake of retinol during chicken oocyte growth. Biochim Biophys Acta 1169:250–256

    PubMed  CAS  Google Scholar 

  16. Hussain MM, Strickland DK, Bakillah A (1999) The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 19:141–172

    Article  PubMed  CAS  Google Scholar 

  17. Sousa MM, Norden AG, Jacobsen C, Willnow TE, Christensen EI, Thakker RV, Verroust PJ, Moestrup SK, Saraiva MJ (2000) Evidence for the role of megalin in renal uptake of transthyretin. J Biol Chem 275:38176–38181

    Article  PubMed  CAS  Google Scholar 

  18. Fleming CE, Mar FM, Franquinho F, Saraiva MJ, Sousa MM (2009) Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci 29:3220–3232

    Article  PubMed  CAS  Google Scholar 

  19. Chang MH, Hua CT, Isaac EL, Litjens T, Hodge G, Karageorgos LE, Meikle PJ (2004) Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in circulation. Biochem J 382:481–489

    Article  PubMed  CAS  Google Scholar 

  20. Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581:3641–3651

    Article  PubMed  CAS  Google Scholar 

  21. Lee AS (1992) Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 4:267–273

    Article  PubMed  CAS  Google Scholar 

  22. Villa A, Podini P, Clegg DO, Pozzan T, Meldolesi J (1991) Intracellular Ca2+ stores in chicken Purkinje neurons: differential distribution of the low affinity-high capacity Ca2+ binding protein, calsequestrin, of Ca2+ ATPase and of the ER lumenal protein, Bip. J Cell Biol 113:779–791

    Article  PubMed  CAS  Google Scholar 

  23. Lievremont JP, Rizzuto R, Hendershot L, Meldolesi J (1997) BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem 272:30873–30879

    Article  PubMed  CAS  Google Scholar 

  24. Macer DR, Koch GL (1988) Identification of a set of calcium-binding proteins in reticuloplasm, the luminal content of the endoplasmic reticulum. J Cell Sci 91(Pt 1):61–70

    PubMed  CAS  Google Scholar 

  25. Liu H, Miller E, van de Water B, Stevens JL (1998) Endoplasmic reticulum stress proteins block oxidant-induced Ca2+ increases and cell death. J Biol Chem 273:12858–12862

    Article  Google Scholar 

  26. McCormick TS, McColl KS, Distelhorst CW (1997) Mouse lymphoma cells destined to undergo apoptosis in response to thapsigargin treatment fail to generate a calcium-mediated grp78/grp94 stress response. J Biol Chem 272:6087–6092

    Article  PubMed  CAS  Google Scholar 

  27. Miyake H, Hara I, Arakawa S, Kamidono S (2000) Stress protein GRP78 prevents apoptosis induced by calcium ionophore, ionomycin, but not by glycosylation inhibitor, tunicamycin, in human prostate cancer cells. J Cell Biochem 77:396–408

    Article  PubMed  CAS  Google Scholar 

  28. Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ (1997) Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem 272:4327–4334

    Article  PubMed  CAS  Google Scholar 

  29. Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS (2003) Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem 278:20915–20924

    Article  PubMed  CAS  Google Scholar 

  30. Kang HS, Welch WJ (1991) Characterization and purification of the 94-kDa glucose-regulated protein. J Biol Chem 266:5643–5649

    PubMed  CAS  Google Scholar 

  31. Lin HY, Masso-Welch P, Di YP, Cai JW, Shen JW, Subjeck JR (1993) The 170-kDa glucose-regulated stress protein is an endoplasmic reticulum protein that binds immunoglobulin. Mol Biol Cell 4:1109–1119

    PubMed  CAS  Google Scholar 

  32. Melnick J, Aviel S, Argon Y (1992) The endoplasmic reticulum stress protein GRP94, in addition to BiP, associates with unassembled immunoglobulin chains. J Biol Chem 267:21303–21306

    PubMed  CAS  Google Scholar 

  33. Meunier L, Usherwood YK, Chung KT, Hendershot LM (2002) A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell 13:4456–4469

    Article  PubMed  CAS  Google Scholar 

  34. Chang L, Munro SL, Richardson SJ, Schreiber G (1999) Evolution of thyroid hormone binding by transthyretins in birds and mammals. Eur J Biochem 259:534–542

    Article  PubMed  CAS  Google Scholar 

  35. Goncalves I, Quintela T, Baltazar G, Almeida MR, Saraiva MJ, Santos CR (2008) Transthyretin interacts with metallothionein 2. Biochemistry 47:2244–2251

    Article  PubMed  CAS  Google Scholar 

  36. Zanotti G, Folli C, Cendron L, Alfieri B, Nishida SK, Gliubich F, Pasquato N, Negro A, Berni R (2008) Structural and mutational analyses of protein–protein interactions between transthyretin and retinol-binding protein. Febs J 275:5841–5854

    Article  PubMed  CAS  Google Scholar 

  37. Sorgjerd K, Ghafouri B, Jonsson BH, Kelly JW, Blond SY, Hammarstrom P (2006) Retention of misfolded mutant transthyretin by the chaperone BiP/GRP78 mitigates amyloidogenesis. J Mol Biol 356:469–482

    Article  PubMed  Google Scholar 

  38. Susuki S, Sato T, Miyata M, Momohara M, Suico MA, Shuto T, Ando Y, Kai H (2009) The Endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells. J Biol Chem 284:8312–8321

    Article  PubMed  CAS  Google Scholar 

  39. Arap MA, Lahdenranta J, Mintz PJ, Hajitou A, Sarkis AS, Arap W, Pasqualini R (2004) Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 6:275–284

    Article  PubMed  CAS  Google Scholar 

  40. Calvert ME, Digilio LC, Herr JC, Coonrod SA (2003) Oolemmal proteomics–identification of highly abundant heat shock proteins and molecular chaperones in the mature mouse egg and their localization on the plasma membrane. Reprod Biol Endocrinol 1:27

    Article  PubMed  Google Scholar 

  41. de Crom R, van Haperen R, Janssens R, Visser P, Willemsen R, Grosveld F, van der Kamp A (1999) Gp96/GRP94 is a putative high-density lipoprotein-binding protein in liver. Biochim Biophys Acta 1437:378–392

    PubMed  Google Scholar 

  42. Delpino A, Castelli M (2002) The 78 kDa glucose-regulated protein (GRP78/BIP) is expressed on the cell membrane, is released into cell culture medium and is also present in human peripheral circulation. Biosci Rep 22:407–420

    Article  PubMed  CAS  Google Scholar 

  43. Reddy RK, Lu J, Lee AS (1999) The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2 +)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. J Biol Chem 274:28476–28483

    Article  PubMed  CAS  Google Scholar 

  44. Robert J, Menoret A, Cohen N (1999) Cell surface expression of the endoplasmic reticular heat shock protein gp96 is phylogenetically conserved. J Immunol 163:4133–4139

    PubMed  CAS  Google Scholar 

  45. Triantafilou M, Fradelizi D, Triantafilou K (2001) Major histocompatibility class one molecule associates with glucose regulated protein (GRP) 78 on the cell surface. Hum Immunol 62:764–770

    Article  PubMed  CAS  Google Scholar 

  46. Wiest DL, Bhandoola A, Punt J, Kreibich G, McKean D, Singer A (1997) Incomplete endoplasmic reticulum (ER) retention in immature thymocytes as revealed by surface expression of “ER-resident” molecular chaperones. Proc Natl Acad Sci USA 94:1884–1889

    Article  PubMed  CAS  Google Scholar 

  47. Misra UK, Gonzalez-Gronow M, Gawdi G, Hart JP, Johnson CE, Pizzo SV (2002) The role of Grp 78 in alpha 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low-density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction. J Biol Chem 277:42082–42087

    Article  PubMed  CAS  Google Scholar 

  48. Misra UK, Gonzalez-Gronow M, Gawdi G, Wang F, Pizzo SV (2004) A novel receptor function for the heat shock protein Grp78: silencing of Grp78 gene expression attenuates alpha2 M*-induced signalling. Cell Signal 16:929–938

    Article  PubMed  Google Scholar 

  49. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47

    Article  PubMed  CAS  Google Scholar 

  50. Brodsky FM, Chen CY, Knuehl C, Towler MC, Wakeham DE (2001) Biological basket weaving: formation and function of clathrin-coated vesicles. Annu Rev Cell Dev Biol 17:517–568

    Article  PubMed  CAS  Google Scholar 

  51. Goldstein JL, Anderson RG, Brown MS (1979) Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature 279:679–685

    Article  PubMed  CAS  Google Scholar 

  52. Trowbridge IS, Collawn JF, Hopkins CR (1993) Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol 9:129–161

    Article  PubMed  CAS  Google Scholar 

  53. Smith SS, Pino RM, Thouron CL (1989) Binding and transport of transthyretin-gold by the endothelium of the rat choriocapillaris. J Histochem Cytochem 37:1497–1502

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof Tomas Kirchhausen, Harvard Medical School, who kindly provided us with dynasore, synthesized by Dr Henry E Pelish. This work was supported by grants from The Family Erling-Persson Foundation, The Swedish Research Council, the Novo Nordisk Foundation, Swedish Diabetes Association, Barndiabetesfonden, Karolinska Institutet, Magnus Bergwalls Foundation, The Knut and Alice Wallenberg Foundation, the Skandia Insurance Company Ltd., VIBRANT (FP7-228933-2), Strategic Research Program in Diabetes at Karolinska Institutet and Berth von Kantzow’s Foundation.

Author information

Authors and Affiliations

  1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1:03, 171 76, Stockholm, Sweden

    Nancy Dekki, Essam Refai, Rebecka Holmberg, Martin Köhler, Per-Olof Berggren & Lisa Juntti-Berggren

  2. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Essam Refai & Hans Jörnvall

Authors
  1. Nancy Dekki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Essam Refai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecka Holmberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Köhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans Jörnvall
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Per-Olof Berggren
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lisa Juntti-Berggren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisa Juntti-Berggren.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dekki, N., Refai, E., Holmberg, R. et al. Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell. Cell. Mol. Life Sci. 69, 1733–1743 (2012). https://doi.org/10.1007/s00018-011-0899-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0899-8

Keywords

Search

Navigation