Herpes simplex virus type 1 (HSV-1) is an important human pathogen and a leading cause of infectious blindness in the developed world. HSV-1 exploits heparan sulfate proteoglycans (HSPG) for attachment to cells. While the significance of heparan sulphate (HS) moieties in HSV-1 infection is well established, the role of specific proteoglycan core proteins in the infection process remains poorly understood. The objective of this study was to assess the roles of syndecan-1 and syndecan-2 core proteins in HSV-1 infection, both of which are expressed by many HSV-1 target cell types. Our results demonstrate that syndecan-1 and syndecan-2 gene silencing by RNA interference reduces HSV-1 entry, plaque formation and facilitates cell survival. Furthermore, HSV-1 infection increases syndecan-1 and syndecan-2 protein synthesis and a resultant increase in cell surface expression of HS. Our observations suggest that changes in syndecan-1 and syndecan-2 expression levels may be related to active viral infection. Taken together, our findings provide new insights into HSPG functions during HSV-1 entry and spread.


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  1. Akhtar, J., Tiwari, V., Oh, M. J., Kovacs, M., Jani, A., Kovacs, S. K., Valyi-Nagy, T. & Shukla, D.(2008). HVEM and nectin-1 are the major mediators of herpes simplex virus 1 (HSV-1) entry into human conjunctival epithelium. Invest Ophthalmol Vis Sci 49, 4026–4035.[CrossRef] [Google Scholar]
  2. Anastasiadou, E., Vaeth, S., Cuomo, L., Boccellato, F., Vincenti, S., Cirone, M., Presutti, C., Junker, S., Winberg, G. & Frati, L.(2009). Epstein–Barr virus infection leads to partial phenotypic reversion of terminally differentiated malignant B cells. Cancer Lett 284, 165–174.[CrossRef] [Google Scholar]
  3. Atanasiu, D., Whitbeck, J. C., Cairns, T. M., Reilly, B., Cohen, G. H. & Eisenberg, R. J.(2007). Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion. Proc Natl Acad Sci U S A 104, 18718–18723.[CrossRef] [Google Scholar]
  4. Barth, H., Schafer, C., Adah, M. I., Zhang, F., Linhardt, R. J., Toyoda, H., Kinoshita-Toyoda, A., Toida, T., Van Kuppevelt, T. H. & other authors(2003). Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J Biol Chem 278, 41003–41012.[CrossRef] [Google Scholar]
  5. Beauvais, D. M., Burbach, B. J. & Rapraeger, A. C.(2004). The syndecan-1 ectodomain regulates αvβ3 integrin activity in human mammary carcinoma cells. J Cell Biol 167, 171–181.[CrossRef] [Google Scholar]
  6. Bobardt, M. D., Chatterji, U., Selvarajah, S., Van der Schueren, B., David, G., Kahn, B. & Gallay, P. A.(2007). Cell-free human immunodeficiency virus type 1 transcytosis through primary genital epithelial cells. J Virol 81, 395–405.[CrossRef] [Google Scholar]
  7. Brule, S., Charnaux, N., Sutton, A., Ledoux, D., Chaigneau, T., Saffar, L. & Gattegno, L.(2006). The shedding of syndecan-4 and syndecan-1 from HeLa cells and human primary macrophages is accelerated by SDF-1/CXCL12 and mediated by the matrix metalloproteinase-9. Glycobiology 16, 488–501.[CrossRef] [Google Scholar]
  8. Burbach, B. J., Friedl, A., Mundhenke, C. & Rapraeger, A. C.(2003). Syndecan-1 accumulates in lysosomes of poorly differentiated breast carcinoma cells. Matrix Biol 22, 163–177.[CrossRef] [Google Scholar]
  9. Carey, D. J.(1997). Syndecans: multifunctional cell-surface co-receptors. Biochem J 327, 1–16. [Google Scholar]
  10. Cheshenko, N., Liu, W., Satlin, L. M. & Herold, B. C.(2007). Multiple receptor interactions trigger release of membrane and intracellular calcium stores critical for herpes simplex virus entry. Mol Biol Cell 18, 3119–3130.[CrossRef] [Google Scholar]
  11. Clement, C., Tiwari, V., Scanlan, P. M., Valyi-Nagy, T., Yue, B. Y. & Shukla, D.(2006). A novel role for phagocytosis-like uptake in herpes simplex virus entry. J Cell Biol 174, 1009–1021.[CrossRef] [Google Scholar]
  12. Copeland, R., Balasubramaniam, A., Tiwari, V., Zhang, F., Bridges, A., Linhardt, R. J., Shukla, D. & Liu, J.(2008). Using a 3-O-sulfated heparin octasaccharide to inhibit the entry of herpes simplex virus type 1. Biochemistry 47, 5774–5783.[CrossRef] [Google Scholar]
  13. Couchman, J. R.(2003). Syndecans: proteoglycan regulators of cell-surface microdomains? Nat Rev Mol Cell Biol 4, 926–938,. [Google Scholar]
  14. Deepa, S. S., Yamada, S., Zako, M., Goldberger, O. & Sugahara, K.(2004). Chondroitin sulfate chains on syndecan-1 and syndecan-4 from normal murine mammary gland epithelial cells are structurally and functionally distinct and cooperate with heparan sulfate chains to bind growth factors. A novel function to control binding of midkine, pleiotrophin, and basic fibroblast growth factor. J Biol Chem 279, 37368–37376.[CrossRef] [Google Scholar]
  15. Desai, P. & Person, S.(1998). Incorporation of the green fluorescent protein into the herpes simplex virus type 1 capsid. J Virol 72, 7563–7568. [Google Scholar]
  16. Esko, J. D. & Lindahl, U.(2001). Molecular diversity of heparan sulfate. J Clin Invest 108, 169–173.[CrossRef] [Google Scholar]
  17. Ethell, I. M., Irie, F., Kalo, M. S., Couchman, J. R., Pasquale, E. B. & Yamaguchi, Y.(2001). EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001–1013.[CrossRef] [Google Scholar]
  18. Freissler, E., Meyer auf der Heyde, A., David, G., Meyer, T. F. & Dehio, C.(2000). Syndecan-1 and syndecan-4 can mediate the invasion of OpaHSPG-expressing Neisseria gonorrhoeae into epithelial cells. Cell Microbiol 2, 69–82.[CrossRef] [Google Scholar]
  19. Fuki, I. V., Meyer, M. E. & Williams, K. J.(2000). Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts. Biochem J 351, 607–612.[CrossRef] [Google Scholar]
  20. Geraghty, R. J., Krummenacher, C., Cohen, G. H., Eisenberg, R. J. & Spear, P. G.(1998). Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science 280, 1618–1620.[CrossRef] [Google Scholar]
  21. Giroglou, T., Florin, L., Schäfer, F., Streeck, R. E. & Sapp, M.(2001). Human papillomavirus infection requires cell surface heparan sulfate. J Virol 75, 1565–1570.[CrossRef] [Google Scholar]
  22. Grootjans, J. J., Zimmermann, P., Reekmans, G., Smets, A., Degeest, G., Dürr, J. & David, G.(1997). Syntenin, a PDZ protein that binds syndecan cytoplasmic domains. Proc Natl Acad Sci U S A 94, 13683–13688.[CrossRef] [Google Scholar]
  23. Herold, B. C., WuDunn, D., Soltys, N. & Spear, P. G.(1991). Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity. J Virol 65, 1090–1098. [Google Scholar]
  24. Hill, J. M. & Clement, C.(2009). Herpes simplex virus type 1 DNA in human corneas: what are the virological and clinical implications? J Infect Dis 200, 1–4.[CrossRef] [Google Scholar]
  25. Kubo, T., Wada, T., Yamaguchi, Y., Shimizu, A. & Handa, H.(2006). Knock-down of 25 kDa subunit of cleavage factor Im in HeLa cells alters alternative polyadenylation within 3′-UTRs. Nucleic Acids Res 34, 6264–6271.[CrossRef] [Google Scholar]
  26. Kumaraguru, U. & Rouse, B. T.(2002). The IL-12 response to herpes simplex virus is mainly a paracrine response of reactive inflammatory cells. J Leukoc Biol 72, 564–570. [Google Scholar]
  27. Lindahl, U., Kusche-Gullberg, M. & Kjellén, L.(1998). Regulated diversity of heparan sulfate. J Biol Chem 273, 24979–24982.[CrossRef] [Google Scholar]
  28. Lopes, C. C., Dietrich, C. P. & Nader, H. B.(2006). Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling. Braz J Med Biol Res 39, 157–167.[CrossRef] [Google Scholar]
  29. Magalhães, A., Marcos, N. T., Carvalho, A. S., David, L., Figueiredo, C., Bastos, J., David, G. & Reis, C. A.(2009).Helicobacter pylori cag pathogenicity island-positive strains induce syndecan-4 expression in gastric epithelial cells. FEMS Immunol Med Microbiol 56, 223–232.[CrossRef] [Google Scholar]
  30. Menozzi, F. D., Reddy, V. M., Cayet, D., Raze, D., Debrie, A. S., Dehouck, M. P., Cecchelli, R. & Locht, C.(2006).Mycobacterium tuberculosis heparin-binding haemagglutinin adhesin (HBHA) triggers receptor-mediated transcytosis without altering the integrity of tight junctions. Microbes Infect 8, 1–9.[CrossRef] [Google Scholar]
  31. Montgomery, R. I., Warner, M. S., Lum, B. J. & Spear, P. G.(1996). Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436.[CrossRef] [Google Scholar]
  32. Muto, T., Miyoshi, K., Munesue, S., Nakada, H., Okayama, M., Matsuo, T. & Noma, T.(2007). Differential expression of syndecan isoforms during mouse incisor amelogenesis. J Med Invest 54, 331–339.[CrossRef] [Google Scholar]
  33. Nicola, A. V., McEvoy, A. M. & Straus, S. E.(2003). Roles for endocytosis and low pH in herpes simplex virus entry into HeLa and Chinese hamster ovary cells. J Virol 77, 5324–5332.[CrossRef] [Google Scholar]
  34. O'Donnell, C. D. & Shukla, D.(2008). The importance of heparan sulfate in herpesvirus infection. Virol Sin 23, 383–393.[CrossRef] [Google Scholar]
  35. O'Donnell, C. D., Kovacs, M., Akhtar, J., Valyi-Nagy, T. & Shukla, D.(2010). Expanding the role of 3-O sulfated heparan sulfate in herpes simplex virus type-1 entry. Virology 397, 389–398.[CrossRef] [Google Scholar]
  36. Rapraeger, A., Jalkanen, M., Endo, E., Koda, J. & Bernfield, M.(1985). The cell surface proteoglycan from mouse mammary epithelial cells bears chondroitin sulfate and heparan sulfate glycosaminoglycans. J Biol Chem 260, 11046–11052. [Google Scholar]
  37. Reske, A., Pollara, G., Krummenacher, C., Chain, B. M. & Katz, D. R.(2007). Understanding HSV-1 entry glycoproteins. Rev Med Virol 17, 205–215.[CrossRef] [Google Scholar]
  38. Schofield, K. P., Gallagher, J. T. & David, G.(1999). Expression of proteoglycan core proteins in human bone marrow stroma. Biochem J 343, 663–668.[CrossRef] [Google Scholar]
  39. Shimabukuro, Y., Ichikawa, T., Terashima, Y., Iwayama, T., Oohara, H., Kajikawa, T., Kobayashi, R., Terashima, H., Takedachi, M. & Terakura, M.(2008). Basic fibroblast growth factor regulates expression of heparan sulfate in human periodontal ligament cells. Matrix Biol 27, 232–241.[CrossRef] [Google Scholar]
  40. Shukla, D. & Spear, P. G.(2001). Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J Clin Invest 108, 503–510.[CrossRef] [Google Scholar]
  41. Shukla, D., Rowe, C. L., Dong, Y., Racaniello, V. R. & Spear, P. G.(1999a). The murine homolog (Mph) of human herpesvirus entry protein B (HveB) mediates entry of pseudorabies virus but not herpes simplex virus types 1 and 2. J Virol 73, 4493–4497. [Google Scholar]
  42. Shukla, D., Liu, J., Blaiklock, P., Shworak, N. W., Bai, X., Esko, J. D., Cohen, G. H., Eisenberg, R. J., Rosenberg, R. D. & Spear, P. G.(1999b). A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry. Cell 99, 13–22.[CrossRef] [Google Scholar]
  43. Shukla, S. Y., Singh, Y. K. & Shukla, D.(2009). Role of nectin-1, HVEM, and PILR-α in HSV-2 entry into human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 50, 2878–2887.[CrossRef] [Google Scholar]
  44. Shworak, N. W., Shirakawa, M., Mulligan, R. C. & Rosenberg, R. D.(1994). Characterization of ryudocan glycosaminoglycan acceptor sites. J Biol Chem 269, 21204–21214. [Google Scholar]
  45. Smith, M. F., Jr, Novotny, J., Carl, V. S. & Comeau, L. D.(2006).Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-κB-dependent manner. Glycobiology 16, 221–229. [Google Scholar]
  46. Spear, P. G., Eisenberg, R. J. & Cohen, G. H.(2000). Three classes of cell surface receptors for alphaherpesvirus entry. Virology 275, 1–8.[CrossRef] [Google Scholar]
  47. Su, G., Blaine, S. A., Qiao, D. & Friedl, A.(2007). Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation. J Biol Chem 282, 14906–14915.[CrossRef] [Google Scholar]
  48. Terasaka, Y., Miyazaki, D., Yakura, K., Haruki, T. & Inoue, Y.(2010). Induction of IL-6 in transcriptional networks in corneal epithelial cells after herpes simplex virus type 1 infection. Invest Ophthalmol Vis Sci 51, 2441–2449.[CrossRef] [Google Scholar]
  49. Tiwari, V., Clement, C., Xu, D., Valyi-Nagy, T., Yue, B. Y., Liu, J. & Shukla, D.(2006). Role for 3-O-sulfated heparan sulfate as the receptor for herpes simplex virus type 1 entry into primary human corneal fibroblasts. J Virol 80, 8970–8980.[CrossRef] [Google Scholar]
  50. Trybala, E., Liljeqvist, J. A., Svennerholm, B. & Bergström, T.(2000). Herpes simplex virus types 1 and 2 differ in their interaction with heparan sulfate. J Virol 74, 9106–9114.[CrossRef] [Google Scholar]
  51. Tumova, S., Woods, A. & Couchman, J. R.(2000). Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. Int J Biochem Cell Biol 32, 269–288.[CrossRef] [Google Scholar]
  52. Wang, S. H., Zhang, C., Liao, C. P., Lasbury, M. E., Durant, P. J., Tschang, D. & Lee, C. H.(2006). Syndecan-1 expression in the lung during Pneumocystis infection. J Eukaryot Microbiol 53 (Suppl. 1), S122–S123.[CrossRef] [Google Scholar]

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