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Leukocyte integrin α4β7 associates with heat shock protein 70

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Abstract

The leukocyte integrin cell adhesion molecules α4β7 and αEβ7 mediate the homing and retention of lymphocytes to the gut, and sites of inflammation. Here we have identified heat shock protein 70 (HSP70) as a major protein that associates with the cytoplasmic domain of the integrin β7 subunit. HSPs are molecular chaperones that protect cells from stress but more recently have been reported to also regulate cell adhesion and invasion via modulation of β1, β2, and β3 integrins and integrin-associated signalling molecules. Several HSP70 isoforms including HSP70-3, HSP70-1L, HSP70-8, and HSP70-9 were specifically precipitated from T cells by a bead-conjugated β7 subunit cytoplasmic domain peptide and subsequently identified by high-resolution liquid chromatography–tandem mass spectrometry. In confirmation, the β7 subunit was co-immunoprecipitated from a T cell lysate by an anti-HSP70 antibody. Further, recombinant human HSP70-1a was precipitated by β7 cytoplasmic domain-coupled beads. The HSP70 inhibitor KNK437 decreased the expression of HSP70 without affecting the expression of the β7 integrin. It significantly inhibited α4β7-mediated adhesion of T cells to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), suggesting HSP70 is critical for maintaining β7 integrin signalling function. The functional implications of the association of β7 integrins with the different isoforms of HSP70 warrants further investigation.

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References

  1. Yuan QA, Jiang WM, Krissansen GW, Watson JD (1990) Cloning and sequence analysis of a novel beta 2-related integrin transcript from T lymphocytes: homology of integrin cysteine-rich repeats to domain III of laminin B chains. Int Immunol 2:1097–1108

    Article  CAS  PubMed  Google Scholar 

  2. Erle DJ, Rüegg C, Sheppard D, Pytela R (1991) Complete amino acid sequence of an integrin beta subunit (beta 7) identified in leukocytes. J Biol Chem 266:11009–11016

    CAS  PubMed  Google Scholar 

  3. Holzmann B, McIntyre BW, Weissman IL (1989) Identification of a murine Peyer’s patch-specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Cell 56:37–46

    Article  CAS  PubMed  Google Scholar 

  4. Gorfu G, Rivera-Nieves J, Ley K (2009) Role of beta7 integrins in intestinal lymphocyte homing and retention. Curr Mol Med 9:836–850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Shaw SK, Brenner MB (1995) The beta 7 integrins in mucosal homing and retention. Semin Immunol 7:335–342

    Article  CAS  PubMed  Google Scholar 

  6. Wagner N, Löhler J, Kunkel EJ, Ley K, Leung E, Krissansen G et al (1996) Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 382:366–370

    Article  CAS  PubMed  Google Scholar 

  7. Wagner N, Müller W (1998) Functions of alpha 4- and beta 7-integrins in hematopoiesis, lymphocyte trafficking and organ development. Curr Top Microbiol Immunol 231:23–32

    CAS  PubMed  Google Scholar 

  8. Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E, Ringler DJ (1997) Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 158:2099–2106

    CAS  PubMed  Google Scholar 

  9. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW et al (2005) Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 352:2499–2507

    Article  CAS  PubMed  Google Scholar 

  10. Sun X, Qiao H, Shi J, Kanwar JR, Mueller W, Wagner N et al (2002) Beta7 integrins contribute to skin graft rejection. Transplantation 74:1202–1203

    Article  CAS  PubMed  Google Scholar 

  11. Kanwar JR, Harrison JE, Wang D, Leung E, Mueller W, Wagner N et al (2000) Beta7 integrins contribute to demyelinating disease of the central nervous system. J Neuroimmunol 103:146–152

    Article  CAS  PubMed  Google Scholar 

  12. Krissansen GW, Print CG, Prestidge RL, Hollander D, Yuan Q, Jiang WM et al (1992) Immunologic and structural relatedness of the integrin beta 7 complex and the human intraepithelial lymphocyte antigen HML-1. FEBS Lett 296:25–28

    Article  CAS  PubMed  Google Scholar 

  13. Parker CM, Cepek KL, Russell GJ, Shaw SK, Posnett DN, Schwarting R et al (1992) A family of beta 7 integrins on human mucosal lymphocytes. Proc Natl Acad Sci USA 89:1924–1928

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Schön MP, Arya A, Murphy EA, Adams CM, Strauch UG, Agace WW et al (1999) Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. J Immunol 162:6641–6649

    PubMed  Google Scholar 

  15. Saibil H (2013) Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol 14:630–642

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Colaco CA, Bailey CR, Walker KB, Keeble J (2013) Heat shock proteins: stimulators of innate and acquired immunity. Biomed Res Int 2013:461230

    Article  PubMed Central  PubMed  Google Scholar 

  17. Wu S, Hong F, Gewirth D, Guo B, Liu B, Li Z (2012) The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain. J Biol Chem 287:6735–6742

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Guerrero CA, Moreno LP (2012) Rotavirus receptor proteins Hsc70 and integrin αvβ3 are located in the lipid microdomains of animal intestinal cells. Acta Virol 56:63–70

    Article  CAS  PubMed  Google Scholar 

  19. Barazi HO, Zhou L, Templeton NS, Krutzsch HC, Roberts DD (2002) Identification of heat shock protein 60 as a molecular mediator of alpha 3 beta 1 integrin activation. Cancer Res 62:1541–1548

    CAS  PubMed  Google Scholar 

  20. Aoyagi Y, Fujita N, Tsuruo T (2005) Stabilization of integrin-linked kinase by binding to HSP90. Biochem Biophys Res Commun 331:1061–1068

    Article  CAS  PubMed  Google Scholar 

  21. Radovanac K, Morgner J, Schulz JN, Blumbach K, Patterson C, Geiger T et al (2013) Stabilization of integrin-linked kinase by the HSP90-CHIP axis impacts cellular force generation, migration and the fibrotic response. EMBO J 32:1409–1424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Xiong X, Wang Y, Liu C, Lu Q, Liu T, Chen G et al (2014) Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells. Exp Cell Res 326:78–89

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Lee JW, Kwak HJ, Lee JJ, Kim YN, Lee JW, Park MJ et al (2008) HSP27 regulates cell adhesion and invasion via modulation of focal adhesion kinase and MMP-2 expression. Eur J Cell Biol 87:377–387

    Article  CAS  PubMed  Google Scholar 

  24. Krissansen GW, Singh J, Kanwar RK, Chan YC, Leung E, Lehnert KB et al (2006) A pseudosymmetric cell adhesion regulatory domain in the beta7 tail of the integrin alpha4beta7 that interacts with focal adhesion kinase and src. Eur J Immunol 36:2203–2214

    Article  CAS  PubMed  Google Scholar 

  25. Yang Y, Sammar M, Harrison JE, Lehnert K, Print CG, Leung E et al (1995) Construction and adhesive properties of a soluble MadCAM-1-Fc chimera expressed in a baculovirus system: phylogenetic conservation of receptor-ligand interaction. Scand J Immunol 42:235–247

    Article  CAS  PubMed  Google Scholar 

  26. Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710

    Article  CAS  PubMed  Google Scholar 

  27. Tavaria M, Gabriele T, Kola I, Anderson RL (1996) A hitchhiker’s guide to the human HSP70 family. Cell Stress Chaperones 1:23–28

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Shiota M, Kusakabe H, Izumi Y, Hikita Y, Nakao T, Funae Y et al (2010) Heat shock cognate protein 70 is essential for Akt signaling in endothelial function. Arterioscler Thromb Vasc Biol 30:491–497

    Article  CAS  PubMed  Google Scholar 

  30. Yokota S, Kitahara M, Nagata K (2000) Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res 60:2942–2948

    CAS  PubMed  Google Scholar 

  31. Nimmanapalli R, Gerbino E, Dalton WS, Gandhi V, Alsina M (2008) HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma. Br J Haematol 142:551–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Murphy ME (2013) The HSP70 family and cancer. Carcinogenesis 34:1181–1188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Powers MV, Clarke PA, Workman P (2008) Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262

    Article  CAS  PubMed  Google Scholar 

  34. Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11:515–528

    Article  CAS  PubMed  Google Scholar 

  35. Morgner J, Wickström SA (2013) The weakest link: a new paradigm for stabilizing the integrin-actin connection. Cell Cycle 12:2929–2930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Wang YH, Li F, Schwartz JH, Flint PJ, Borkan SC (2001) c-Src and HSP72 interact in ATP-depleted renal epithelial cells. Am J Physiol Cell Physiol 281:C1667–C1675

    CAS  PubMed  Google Scholar 

  37. Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP et al (2013) C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene 32:3101–3110

    Article  CAS  PubMed  Google Scholar 

  38. Evans SS, Bain MD, Wang W-C (2000) Fever-range hyperthermia stimulates α4β7 integrin-dependent lymphocyte-endothelial adhesion. Int J Hyperthermia 16:45–59

    Article  CAS  PubMed  Google Scholar 

  39. Evans SS, Wang WC, Bain MD, Burd R, Ostberg JR, Repasky EA (2001) Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood 97:2727–2733

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Marsden Fund, Royal Society of New Zealand; the Faculty of Medical and Health Sciences, University of Auckland from funding targeted for postgraduate research; the Maurice and Phyllis Paykel Trust; the Sir John Logan Campbell Medical Trust; and the Faculty of Medical and Health Sciences Postgraduate Students’ Association, University of Auckland.

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Authors and Affiliations

  1. Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand

    Yih-Chih Chan, Yi Yang, Euphemia Leung & Geoffrey W. Krissansen

  2. Faculty of Science, School of Biological Sciences, University of Auckland, Auckland, New Zealand

    David R. Greenwood

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  1. Yih-Chih Chan
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  2. David R. Greenwood
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  3. Yi Yang
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Correspondence to Geoffrey W. Krissansen.

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Chan, YC., Greenwood, D.R., Yang, Y. et al. Leukocyte integrin α4β7 associates with heat shock protein 70. Mol Cell Biochem 409, 263–269 (2015). https://doi.org/10.1007/s11010-015-2530-z

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  • DOI: https://doi.org/10.1007/s11010-015-2530-z

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