Host Molecular Chaperones: Cell Surface Receptors for Viruses

  • Tomoyuki Honda
  • Keizo Tomonaga
Part of the Heat Shock Proteins book series (HESP, volume 7)


Molecular chaperones play important roles in maintaining cellular homeostasis under normal conditions. They also participate in a post-translational quality control system, maintaining the correct conformation of proteins under changing environmental conditions. While most molecular chaperones localize in the cytosol, some can exist outside the cell and are involved in moonlighting activities. It has been reported that some molecular chaperones at the cell surface act as receptors for viruses. Viruses using molecular chaperones as their receptors take advantage of these molecules to enable efficient introduction of their genomes into the cell and/or for selection of favorable target cells and of replication-competent virions.


Lipid Raft Molecular Chaperone Japanese Encephalitis Virus Measle Virus Virus Entry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Grants-in-Aid for Young Scientists (KAKENHI) from Japan Society for the Promotion of Science (JSPS) (JSPS KAKENHI Grant Numbers 23790496 and 25860336 T.H.), and Funding Program for Next Generation World-Leading Researchers (NEXT program) from JSPS (K.T.).


  1. Ahn SG, Kim SA, Yoon JH, Vacratsis P (2005) Heat-shock cognate 70 is required for the activation of heat-shock factor 1 in mammalian cells. Biochem J 392:145–152PubMedCrossRefGoogle Scholar
  2. Ali KS, Dorgai L, Abrahám M, Hermesz E (2003) Tissue- and stressor-specific differential expression of two hsc70 genes in carp. Biochem Biophys Res Commun 307:503–509PubMedCrossRefGoogle Scholar
  3. Bajramovic JJ, Münter S, Syan S, Nehrbass U, Brahic M, Gonzalez-Dunia D (2003) Borna disease virus glycoprotein is required for viral dissemination in neurons. J Virol 77:12222–12231PubMedCrossRefGoogle Scholar
  4. Banerjee M, Johnson JE (2008) Activation, exposure and penetration of virally encoded, membrane-active polypeptides during non-enveloped virus entry. Curr Protein Pept Sci 9:16–27PubMedCrossRefGoogle Scholar
  5. Bloor S, Maelfait J, Krumbach R, Beyaert R, Randow F (2010) Endoplasmic reticulum chaperone gp96 is essential for infection with vesicular stomatitis virus. Proc Natl Acad Sci U S A 107:6970–6975PubMedCrossRefGoogle Scholar
  6. Brown CR, Martin RL, Hansen WJ, Beckmann RP, Welch WJ (1993) The constitutive and stress inducible forms of Hsp 70 exhibit functional similarities and interact with one another in an ATP-dependent fashion. J Cell Biol 120:1101–1112PubMedCrossRefGoogle Scholar
  7. Buchholz CJ, Schneider U, Devaux P, Gerlier D, Cattaneo R (1996) Cell entry by measles virus: long hybrid receptors uncouple binding from membrane fusion. J Virol 70:3716–3723PubMedGoogle Scholar
  8. Byrd CA, Bornmann W, Erdjument-Bromage H, Tempst P, Pavletich N, Rosen N, Nathan CF, Ding A (1999) Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide. Proc Natl Acad Sci U S A 96:5645–5650PubMedCrossRefGoogle Scholar
  9. Cabrera-Hernandez A, Thepparit C, Suksanpaisan L, Smith DR (2007) Dengue virus entry into liver (HepG2) cells is independent of hsp90 and hsp70. J Med Virol 79:386–392PubMedCrossRefGoogle Scholar
  10. Carsillo T, Carsillo M, Niewiesk S, Vasconcelos D, Oglesbee M (2004) Hyperthermic pre-conditioning promotes measles virus clearance from brain in a mouse model of persistent infection. Brain Res 1004:73–82PubMedCrossRefGoogle Scholar
  11. Carsillo T, Traylor Z, Choi C, Niewiesk S, Oglesbee M (2006) Hsp72, a host determinant of measles virus neurovirulence. J Virol 80:11031–11039PubMedCrossRefGoogle Scholar
  12. Chavez-Salinas S, Ceballos-Olvera I, Reyes-Del Valle J, Medina F, Del Angel RM (2008) Heat shock effect upon dengue virus replication into U937 cells. Virus Res 138:111–118PubMedCrossRefGoogle Scholar
  13. Clemente R, de Parseval A, Perez M, de la Torre JC (2009) Borna disease virus requires cholesterol in both cellular membrane and viral envelope for efficient cell entry. J Virol 83:2655–2662PubMedCrossRefGoogle Scholar
  14. Das S, Laxminarayana SV, Chandra N, Ravi V, Desai A (2009) Heat shock protein 70 on Neuro2a cells is a putative receptor for Japanese encephalitis virus. Virology 385:47–57PubMedCrossRefGoogle Scholar
  15. de Haan CA, Li Z, te Lintelo E, Bosch BJ, Haijema BJ, Rottier PJ (2005) Murine coronavirus with an extended host range uses heparan sulfate as an entry receptor. J Virol 79:14451–14456PubMedCrossRefGoogle Scholar
  16. Ellis RJ (1997) Do molecular chaperones have to be proteins? Biochem Biophys Res Commun 238:687–692PubMedCrossRefGoogle Scholar
  17. Fischer G, Aumüller T (2003) Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev Physiol Biochem Pharmacol 148:105–150PubMedCrossRefGoogle Scholar
  18. Galat A (2004) Function-dependent clustering of orthologues and paralogues of cyclophilins. Proteins 56:808–820PubMedCrossRefGoogle Scholar
  19. Gerlier D (2011) Emerging zoonotic viruses: new lessons on receptor and entry mechanisms. Curr Opin Virol 1:27–34PubMedCrossRefGoogle Scholar
  20. Goldfarb SB, Kashlan OB, Watkins JN, Suaud L, Yan W, Kleyman TR, Rubenstein RC (2006) Differential effects of Hsc70 and Hsp70 on the intracellular trafficking and functional expression of epithelial sodium channels. Proc Natl Acad Sci U S A 103:5817–5822PubMedCrossRefGoogle Scholar
  21. Gonzalez-Dunia D, Cubitt B, de la Torre JC (1998) Mechanism of Borna disease virus entry into cells. J Virol 72:783–788PubMedGoogle Scholar
  22. Gonzalez-Gronow M, Kaczowka SJ, Payne S, Wang F, Gawdi G, Pizzo SV (2007) Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or the voltage-dependent anion channel. J Biol Chem 282:32811–32820PubMedCrossRefGoogle Scholar
  23. Gosztonyi G, Ludwig H (2001) Interactions of viral proteins with neurotransmitter receptors may protect or destroy neurons. Curr Top Microbiol Immunol 253:121–144PubMedCrossRefGoogle Scholar
  24. Grove J, Marsh M (2011) The cell biology of receptor-mediated virus entry. J Cell Biol 195:1071–1082PubMedCrossRefGoogle Scholar
  25. Guerrero CA, Méndez E, Zárate S, Isa P, López S, Arias CF (2000) Integrin alpha(v)beta(3) mediates rotavirus cell entry. Proc Natl Acad Sci U S A 97:14644–14649PubMedCrossRefGoogle Scholar
  26. Guerrero CA, Bouyssounade D, Zárate S, Isa P, López T, Espinosa R, Romero P, Méndez E, López S, Arias CF (2002) Heat shock cognate protein 70 is involved in rotavirus cell entry. J Virol 76:4096–4102PubMedCrossRefGoogle Scholar
  27. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226:544–547PubMedCrossRefGoogle Scholar
  28. Hashiguchi T, Ose T, Kubota M, Maita N, Kamishikiryo J, Maenaka K, Yanagi Y (2011) Structure of the measles virus hemagglutinin bound to its cellular receptor SLAM. Nat Struct Mol Biol 18:135–141PubMedCrossRefGoogle Scholar
  29. Henderson B, Martin A (2011) Bacterial virulence in the moonlight: multitasking bacterial moonlighting proteins are virulence determinants in infectious disease. Infect Immun 79:3476–3491PubMedCrossRefGoogle Scholar
  30. Henderson B, Allan E, Coates AR (2006) Stress wars: the direct role of host and bacterial molecular chaperones in bacterial infection. Infect Immun 74:3693–3706PubMedCrossRefGoogle Scholar
  31. Hewish MJ, Takada Y, Coulson BS (2000) Integrins alpha2beta1 and alpha4beta1 can mediate SA11 rotavirus attachment and entry into cells. J Virol 74:228–236PubMedCrossRefGoogle Scholar
  32. Hogle JM (2002) Poliovirus cell entry: common structural themes in viral cell entry pathways. Annu Rev Microbiol 56:677–702PubMedCrossRefGoogle Scholar
  33. Honda T, Horie M, Daito T, Ikuta K, Tomonaga K (2009) Molecular chaperone BiP interacts with Borna disease virus glycoprotein at the cell surface. J Virol 83:12622–12625PubMedCrossRefGoogle Scholar
  34. Huet C, Ash JF, Singer SJ (1980) The antibody-induced clustering and endocytosis of HLA antigens on cultured human fibroblasts. Cell 21:429–438PubMedCrossRefGoogle Scholar
  35. Jindadamrongwech S, Thepparit C, Smith DR (2004) Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Arch Virol 149:915–927PubMedCrossRefGoogle Scholar
  36. Kalia M, Jameel S (2011) Virus entry paradigms. Amino Acids 41:1147–1157PubMedCrossRefGoogle Scholar
  37. Kambara H, Tani H, Mori Y, Abe T, Katoh H, Fukuhara T, Taguwa S, Moriishi K, Matsuura Y (2011) Involvement of cyclophilin B in the replication of Japanese encephalitis virus. Virology 412:211–219PubMedCrossRefGoogle Scholar
  38. Kim KB, Lee JW, Lee CS, Kim BW, Choo HJ, Jung SY, Chi SG, Yoon YS, Yoon G, Ko YG (2006) Oxidation-reduction respiratory chains and ATP synthase complex are localized in detergent-resistant lipid rafts. Proteomics 6:2444–2453PubMedCrossRefGoogle Scholar
  39. Lee AS (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26:504–510PubMedCrossRefGoogle Scholar
  40. Lee J, Kim SS (2010) Current implications of cyclophilins in human cancers. J Exp Clin Cancer Res 29:97PubMedCrossRefGoogle Scholar
  41. Liberek K, Lewandowska A, Zietkiewicz S (2008) Chaperones in control of protein disaggregation. EMBO J 27:328–335PubMedCrossRefGoogle Scholar
  42. Ludwig H, Bode L (2000) Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology. Rev Sci Tech 19:259–288PubMedGoogle Scholar
  43. Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977PubMedCrossRefGoogle Scholar
  44. Machy P, Truneh A, Gennaro D, Hoffstein S (1987) Endocytosis and de novo expression of major histocompatibility complex encoded class I molecules: kinetic and ultrastructural studies. Eur J Cell Biol 45:126–136PubMedGoogle Scholar
  45. Marsh M, Helenius A (2006) Virus entry: open sesame. Cell 124:729–740PubMedCrossRefGoogle Scholar
  46. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684PubMedCrossRefGoogle Scholar
  47. Mercer J, Schelhaas M, Helenius A (2010) Virus entry by endocytosis. Annu Rev Biochem 79:803–833PubMedCrossRefGoogle Scholar
  48. Misra UK, Pizzo SV (2008) Heterotrimeric Galphaq11 co-immunoprecipitates with surface-anchored GRP78 from plasma membranes of alpha2M*-stimulated macrophages. J Cell Biochem 104:96–104PubMedCrossRefGoogle Scholar
  49. Misra UK, Chu CT, Gawdi G, Pizzo SV (1994) Evidence for a second alpha 2-macroglobulin receptor. J Biol Chem 269:12541–12547PubMedGoogle Scholar
  50. 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 277:42082–42087PubMedCrossRefGoogle Scholar
  51. Modis Y, Ogata S, Clements D, Harrison SC (2003) A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci U S A 100:6986–6991PubMedCrossRefGoogle Scholar
  52. Modis Y, Ogata S, Clements D, Harrison SC (2004) Structure of the dengue virus envelope protein after membrane fusion. Nature 427:313–319PubMedCrossRefGoogle Scholar
  53. Modis Y, Ogata S, Clements D, Harrison SC (2005) Variable surface epitopes in the crystal structure of dengue virus type 3 envelope glycoprotein. J Virol 79:1223–1231PubMedCrossRefGoogle Scholar
  54. Moss WJ, Griffin DE (2006) Global measles elimination. Nat Rev Microbiol 4:900–908PubMedCrossRefGoogle Scholar
  55. Navarro-Sanchez E, Altmeyer R, Amara A, Schwartz O, Fieschi F, Virelizier JL, Arenzana-Seisdedos F, Desprès P (2003) Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep 4:723–728PubMedCrossRefGoogle Scholar
  56. Pelham HR (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46:959–961PubMedCrossRefGoogle Scholar
  57. Pelkmans L, Helenius A (2003) Insider information: what viruses tell us about endocytosis. Curr Opin Cell Biol 15:414–422PubMedCrossRefGoogle Scholar
  58. Perez M, Watanabe M, Whitt MA, de la Torre JC (2001) N-terminal domain of Borna disease virus G (p56) protein is sufficient for virus receptor recognition and cell entry. J Virol 75:7078–7085PubMedCrossRefGoogle Scholar
  59. Pérez-Vargas J, Romero P, López S, Arias CF (2006) The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J Virol 80:3322–3331PubMedCrossRefGoogle Scholar
  60. Reyes-Del Valle J, Chávez-Salinas S, Medina F, Del Angel RM (2005) Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells. J Virol 79:4557–4567PubMedCrossRefGoogle Scholar
  61. Richt JA, Fürbringer T, Koch A, Pfeuffer I, Herden C, Bause-Niedrig I, Garten W (1998) Processing of the Borna disease virus glycoprotein gp94 by the subtilisin-like endoprotease furin. J Virol 72:4528–4533PubMedGoogle Scholar
  62. Rohde M, Daugaard M, Jensen MH, Helin K, Nylandsted J, Jäättelä M (2005) Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 19:570–582PubMedCrossRefGoogle Scholar
  63. Roivainen M, Piirainen L, Hovi T, Virtanen I, Riikonen T, Heino J, Hyypiä T (1994) Entry of coxsackievirus A9 into host cells: specific interactions with alpha v beta 3 integrin, the vitronectin receptor. Virology 203:357–365PubMedCrossRefGoogle Scholar
  64. Rubio ME, Wenthold RJ (1999) Calnexin and the immunoglobulin binding protein (BiP) coimmunoprecipitate with AMPA receptors. J Neurochem 73:942–948PubMedCrossRefGoogle Scholar
  65. Sato H, Yoneda M, Honda T, Kai C (2012) Morbillivirus receptors and tropism: multiple pathways for infection. Front Microbiol 3:75PubMedGoogle Scholar
  66. Schmid FX (1993) Prolyl isomerase: enzymatic catalysis of slow protein-folding reactions. Annu Rev Biophys Biomol Struct 22:123–142PubMedCrossRefGoogle Scholar
  67. Strebel K, Luban J, Jeang KT (2009) Human cellular restriction factors that target HIV-1 replication. BMC Med 7:48PubMedCrossRefGoogle Scholar
  68. Su HL, Liao CL, Lin YL (2002) Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol 76:4162–4171PubMedCrossRefGoogle Scholar
  69. Tassaneetrithep B, Burgess TH, Granelli-Piperno A, Trumpfheller C, Finke J, Sun W, Eller MA, Pattanapanyasat K, Sarasombath S, Birx DL, Steinman RM, Schlesinger S, Marovich MA (2003) DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 197:823–829PubMedCrossRefGoogle Scholar
  70. Tatsuo H, Ono N, Tanaka K, Yanagi Y (2000) SLAM (CDw150) is a cellular receptor for measles virus. Nature 406:893–897PubMedCrossRefGoogle Scholar
  71. Thepparit C, Smith DR (2004) Serotype-specific entry of dengue virus into liver cells: identification of the 37-kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor. J Virol 78:12647–12656PubMedCrossRefGoogle Scholar
  72. Thongtan T, Wikan N, Wintachai P, Rattanarungsan C, Srisomsap C, Cheepsunthorn P, Smith DR (2012) Characterization of putative Japanese encephalitis virus receptor molecules on microglial cells. J Med Virol 84:615–623PubMedCrossRefGoogle Scholar
  73. Tomonaga K, Kobayashi T, Ikuta K (2002) Molecular and cellular biology of Borna disease virus infection. Microbes Infect 4:491–500PubMedCrossRefGoogle Scholar
  74. Triantafilou K, Triantafilou M (2003) Lipid raft microdomains: key sites for Coxsackievirus A9 infectious cycle. Virology 317:128–135PubMedCrossRefGoogle Scholar
  75. Triantafilou M, Triantafilou K, Wilson KM, Takada Y, Fernandez N, Stanway G (1999) Involvement of beta2-microglobulin and integrin alphavbeta3 molecules in the coxsackievirus A9 infectious cycle. J Gen Virol 80(Pt 10):2591–2600PubMedGoogle Scholar
  76. Triantafilou K, Triantafilou M, Dedrick RL (2001) A CD14-independent LPS receptor cluster. Nat Immunol 2:338–345PubMedCrossRefGoogle Scholar
  77. Triantafilou K, Fradelizi D, Wilson K, Triantafilou M (2002) GRP78, a coreceptor for coxsackievirus A9, interacts with major histocompatibility complex class I molecules which mediate virus internalization. J Virol 76:633–643PubMedCrossRefGoogle Scholar
  78. Valyi-Nagy T, Dermody TS (2005) Role of oxidative damage in the pathogenesis of viral infections of the nervous system. Histol Histopathol 20:957–967PubMedGoogle Scholar
  79. Vlasak M, Goesler I, Blaas D (2005) Human rhinovirus type 89 variants use heparan sulfate proteoglycan for cell attachment. J Virol 79:5963–5970PubMedCrossRefGoogle Scholar
  80. Vogel M, Bukau B, Mayer MP (2006) Allosteric regulation of Hsp70 chaperones by a proline switch. Mol Cell 21:359–367PubMedCrossRefGoogle Scholar
  81. Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:226PubMedCrossRefGoogle Scholar
  82. Watanabe A, Yoneda M, Ikeda F, Terao-Muto Y, Sato H, Kai C (2010) CD147/EMMPRIN acts as a functional entry receptor for measles virus on epithelial cells. J Virol 84:4183–4193PubMedCrossRefGoogle Scholar
  83. Whittaker GR, Helenius A (1998) Nuclear import and export of viruses and virus genomes. Virology 246:1–23PubMedCrossRefGoogle Scholar
  84. Ylinen LM, Schaller T, Price A, Fletcher AJ, Noursadeghi M, James LC, Towers GJ (2009) Cyclophilin A levels dictate infection efficiency of human immunodeficiency virus type 1 capsid escape mutants A92E and G94D. J Virol 83:2044–2047PubMedCrossRefGoogle Scholar
  85. Zhang W, Chipman PR, Corver J, Johnson PR, Zhang Y, Mukhopadhyay S, Baker TS, Strauss JH, Rossmann MG, Kuhn RJ (2003) Visualization of membrane protein domains by cryo-electron microscopy of dengue virus. Nat Struct Biol 10:907–912PubMedCrossRefGoogle Scholar
  86. Zhu YZ, Cao MM, Wang WB, Wang W, Ren H, Zhao P, Qi ZT (2012) Association of heat-shock protein 70 with lipid rafts is required for Japanese encephalitis virus infection in Huh7 cells. J Gen Virol 93:61–71PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Viral Oncology, Institute for Virus ResearchKyoto UniversityKyotoJapan

Personalised recommendations