Medical Microbiology and Immunology

, Volume 193, Issue 4, pp 155–162

The functional interaction between CD98 and CD147 in regulation of virus-induced cell fusion and osteoclast formation

  • Kouki Mori
  • Makoto Nishimura
  • Masato Tsurudome
  • Morihiro Ito
  • Machiko Nishio
  • Mitsuo Kawano
  • Yuuji Kozuka
  • Yasufumi Yamashita
  • Hiroshi Komada
  • Atsumasa Uchida
  • Yasuhiko Ito
Original Investigation

Abstract

Membrane fusion is an important event in the functioning of a living organism. Life starts as a sperm fuses with the membrane of an egg, leading to its fertilization. Membrane fusion is also required for myogenesis, osteogenesis and placenta formation. Multinucleated giant cells originating from monocytes-macrophages are associated with granulomatous lesions formed in response to foreign bodies, viruses, and bacteria. The CD4 molecule acts as a receptor for HIV. The major virus envelope glycoprotein, gp120, attaches to CD4 molecules expressed on the host cell surface. After binding to CD4 on the target cells, HIV is internalized via direct, pH-independent fusion of the viral and cell membranes. However, attachment of HIV to CD4 on the target cells is not sufficient for fusion. Interaction of gp160-expressing cells with neighboring cells bearing surface CD4 molecules is also required for syncytium formation. Syncytium formation and subsequent generalized cell fusion have been reported as potentially important mechanisms of virus-induced cytotoxic effects. Some antibodies against CD98/FRP-1 suppressed virus-induced cell fusion and CD98-mediated cell fusion of monocytes, indicating that CD98/FRP-1 molecules are able to regulate cell fusion. In this study, the functional interaction between CD98 and CD147 was investigated. Three kinds (Ab1, 2, and 3) of anti-CD147 and three kinds of anti-CD98 antibodies were used. Ab1 suppressed CD98-mediated cell fusion, but showed no effect on cell aggregation of Cd+U2ME-7 cells, U937–2 cells expressing HIV gp160. On the other hand, Ab2 enhanced the CD98-mediated cell fusion. Ab1 showed suppressive effect at early stage and Ab2 showed enhancing effect at later stage. Ab2 and 3 suppressed the spontaneous cell agglutination and cell fusion of Cd+JME-2 cells, Jurkat cells expressing HIV gp160. Ab2 suppressed CD98-mediated cell fusion, but showed no effect on cell aggregation of Cd+JME-2 cells. Ab2 cancelled suppression of cell fusion induced by suppressive antibody against CD98. Ab2 and 3 also suppressed CD98-mediated cell fusion of monocytes. This study indicates the functional interaction between CD98 and CD147 in the regulation of cell fusion.

Keywords

CD98 FRP-1 CD147 Cell fusion HIV 

References

  1. 1.
    Berditchevski F, Chang S, Bodorova J, Hemler ME (1997) Generation of monoclonal antibodies to integrin-assocoated proteins: evidence that alpha3beta1 complexes with EMMPRIN/basigin/OX47/M6. J Biol Chem 272:29174–29180CrossRefPubMedGoogle Scholar
  2. 2.
    Burger KN Verkleij AJ (1990) Membrane fusion. Experientia 46:631–644PubMedGoogle Scholar
  3. 3.
    Cho JK, Fox DA, Horejsi V, Sagawa K, Skubitz KM, Katz DR, Chain B (2001) The functional interactions between CD98, beta1-integrins, and CD147 in the induction of U937 homotypic aggregation. Blood 98:374–382CrossRefPubMedGoogle Scholar
  4. 4.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135–1148PubMedGoogle Scholar
  5. 5.
    Dalgleish AG, Beverly PCL, Clapham PR, Crawford DH, Greaves MF, Weiss RA (1984) The CD4 (T-4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312:763–766PubMedGoogle Scholar
  6. 6.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666PubMedGoogle Scholar
  7. 7.
    Fadool JM, Linser PJ (1993) 5A11 antigen is a cell recognition molecule which is involved in neuronal-glial interactions in avian neural retina. Dev Dyn 196:252–262PubMedGoogle Scholar
  8. 8.
    Feng Y. Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272:872–877Google Scholar
  9. 9.
    Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343:281–299PubMedGoogle Scholar
  10. 10.
    Higuchi S, Tabata N, Tajima M, Ito M, Tsurudome M, Sudo A, Uchida A, Ito Y (1998) Induction of human osteoclast-like cells by treatment of blood monocytes with anti-fusion regulatory protein-1/CD98 monoclonal antibodies. J Bone Miner Res 13:44–49PubMedGoogle Scholar
  11. 11.
    Higuchi Y, It M, Tajima M, Higuchi S, Miyamoto N, Nishio M, Kawano M, Kusagawa S, Tsurudome M, Sudo A, Kato K, Uchida A, Ito Y (1999) Gene expression during process of osteoclast-like cell formation induced by anti-fusion regulatory protein-1/CD98/4F2 monoclonal antibodies: c-src is selectively induced by anti-FRP-1 mAb. Bone 25:17–24CrossRefPubMedGoogle Scholar
  12. 12.
    Igakura T, Kadomatsu K, Taguchi O, Muramatsu H, Kaname T, Miyauchi T, Yamamura K, Arimura K, Muramatsu T (1996) Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response. Biochem Biophys Res Commun 224:33–36CrossRefPubMedGoogle Scholar
  13. 13.
    Kasinrerk W, Tokrasinwit N, Phunpae P (1999) CD147 monoclonal antibodies induce homotypic cell aggregation of monocytic cell line U937 via LFA-1/ICAM-1 pathway. Immunology 96:184–192CrossRefPubMedGoogle Scholar
  14. 14.
    Khunkeawla P, Moonsom S, Straffler G, Kongtawelert P, Kasinrerk W (2001) Engagement of CD147 molecule-induced cell aggregation through the activation of protein kinases and reorganization of the cytoskeleton. Immunobiology 203:659–669PubMedGoogle Scholar
  15. 15.
    Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP (2000) CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 19:3896–3904PubMedGoogle Scholar
  16. 16.
    Kirsch AH, Diaz LA Jr, Bonish B, Antony PA, Fox DA (1997) The pattern of expression of CD147/neurothelin during human T-cell ontogeny as defined by the monoclonal antibody 8D6.Tissue Antigens 50:147–152PubMedGoogle Scholar
  17. 17.
    Klatzmann D, Champagne E, Chamaret S, Gruest J, Guéstard D, Hercend T, Gluckmann J C, Montagnier L (1984) T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 312:767–768PubMedGoogle Scholar
  18. 18.
    Koga Y, Sasaki M, Yoshida H, Wigzell H, Kimura G, Nomoto, K (1990) Cytopathic effect determined by the amount of CD4 molecules in human cell lines expressing envelope glycoprotein of HIV. J Immunol 144: 94-102PubMedGoogle Scholar
  19. 19.
    Koot M, Keet IPM, Vos AHV, Goede REY, Roos MTL, Coutinho RA, Miedema F, Schellekens PTA Tersmette M (1993) Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 118:681–688PubMedGoogle Scholar
  20. 20.
    Lifson JD, Feinberg MB, Reyes GR, Rabin L, Banapour B, Chakrabarti S. Moss B, Wong-Staal F, Steimer KS, Engleman EG (1986) Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature 323:725–728PubMedGoogle Scholar
  21. 21.
    Lifson JD, Reyes GR, McGrath MS, Stein BS, Engleman EG (1986) AIDS retrovirus induced cytopathology: giant cell formation and involvement of CD4 antigen. Science 232:1123–1127PubMedGoogle Scholar
  22. 22.
    Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R (1988) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47:333–348Google Scholar
  23. 23.
    McClure MO, Marsh M, Weiss RA (1998) Human immunodeficiency virus infection of CD4-bearing cells occurs by a pH-independent mechanism. EMBO J 7:513–518Google Scholar
  24. 24.
    Namba K, Nishio M, Mori K, Miyamoto N. Tsurudome M, Ito M, Kawano M, Uchida A, Ito Y (2001) Involvement of ADAM9 in multinucleated giant cell formation of blood monocytes. Cell Immunol 213:104–113CrossRefPubMedGoogle Scholar
  25. 25.
    Ohgimoto, S, Tabata N, Suga S, Nishio M, Ohta H, Tsurudome M, Komada H, Kawano M, Watanabe N, Ito Y (1995) Molecular characterization of fusion regulatory protein-1 (FRP-1) that induces multinucleated giant cell formation of monocytes and HIV gp160-mediated cell fusion. J Immunol 135:3585–3592Google Scholar
  26. 26.
    Ohta, H, Tsurudome M, Matsumura H, Koga Y, Morikawa S, Kawano M, Kusagawa S, Komada H, Nishio M, Ito Y (1994) Molecular and biological characterization of fusion regulatory proteins (FRPs): anti-FRP mAbs induced HIV-mediated cell fusion via an integrin system. EMBO J 13:2044–2055PubMedGoogle Scholar
  27. 27.
    Okamoto K, Tsurudome M, Ohgimoto S, Kawano M, Nishio M, Komada H, Ito M, Sakakura Y, Ito Y (1997) An anti-fusion regulatory protein-1 monoclonal antibody suppresses human parainfluenza virus type 2-induced cell fusion. J Gen Virol 78:83–89PubMedGoogle Scholar
  28. 28.
    Seulberger H, Lottspeich F, Risau W (1990) The inducible blood-brain barrier specific molecule HT7 is a novel immunoglobulin-like cell surface glycoprotein. EMBO J 9: 2151–2158PubMedGoogle Scholar
  29. 29.
    Sodroski J, Goh WC, Rosen C, Dayton A, Terwilliger E, Haseltine WA (1986) Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature 322: 470–474PubMedGoogle Scholar
  30. 30.
    Stein BS, Gowda SD, Lifson JD, Penhallow RC, Bensch KG, Engleman EG (1987) pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane. Cell 49:659–668PubMedGoogle Scholar
  31. 31.
    Stonehouse TJ, Woodhead VE, Herridge PS, Ashrafian H, George M, Chain BM, Katz DR (1999) Molecular characterization of U937-dependent T-cell co-stimulation. Immunology 96:35–47CrossRefPubMedGoogle Scholar
  32. 32.
    Suga K, Katagiri K, Kinashi T, Harazaki M, Iizuka T, Hattori M, Minato N (2001) CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap1. FEBS Lett 489:249–253CrossRefPubMedGoogle Scholar
  33. 33.
    Suga S, Tsurudome M, Ohgimoto S, Tanata N, Watanabe N, Nishio M, Kawano M, Ito Y (1995) Identification of fusion regulatory protein (FRP)-1/4F2 related molecules: cytoskeletal proteins are associated with FRP-1 molecules that regulate multinucleated giant cell formation of monocytes and HIV-induced cell fusion. Cell Struct Funct 20:473–483PubMedGoogle Scholar
  34. 34.
    Tabata N, Ito M, Shimokata K, Suga S, Ohgimoto S, Tsurudome M, Kawano M, Matsumura H, Komada H, Nishio M, Ito Y (1995) Expression of fusion regulatory proteins (FRPs) on human peripheral blood monocytes. J Immunol 153:3256–3266Google Scholar
  35. 35.
    Tsurudome M, Ito Y (2000) Function of fusion regulatory proteins (FRPs) in immune cells and virus-infected cells. Crit Rev Immunol 20:167–196PubMedGoogle Scholar
  36. 36.
    Tsurudome M, Ito M, Takebayashi S, Okumura K, Nishio M, Kawano M, Kusagawa S, Komada H, Ito Y (1999) Primary structure of the light chain of fusion regulatory protein-1/CD98/4F2 predicts a protein with multiple transmembrane domains that is almost identical to the amino acid transporter E16. J Immunol 162:2462–2466PubMedGoogle Scholar
  37. 37.
    White JM (1990) Viral and cellular membrane fusion protein. Annu Rev Physiol 52:675–697CrossRefPubMedGoogle Scholar
  38. 38.
    Woodhead VE, Stonehouse TJ, Binks MH, Speide LK, Fox DA, Gaya A, Hardie D, Henniker AJ. Horejsi V, Sagawa K, Skubitz KM, Taskov H, Todd RF 3rd, Agthoven A van, Katz DR, Chain BM (2000) Novel molecular mechanisms of dendritic cell-induced T cell activation. Int Immunol 12:1051–1061CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Kouki Mori
    • 1
    • 2
  • Makoto Nishimura
    • 1
    • 2
  • Masato Tsurudome
    • 1
  • Morihiro Ito
    • 1
  • Machiko Nishio
    • 1
  • Mitsuo Kawano
    • 1
  • Yuuji Kozuka
    • 1
  • Yasufumi Yamashita
    • 1
  • Hiroshi Komada
    • 1
  • Atsumasa Uchida
    • 2
  • Yasuhiko Ito
    • 1
  1. 1.Department of MicrobiologyMie University School of MedicineMie PrefectureJapan
  2. 2.Department of OrthopaedicsMie University School of MedicineMie PrefectureJapan

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