Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 May;71(5):4042–4054. doi: 10.1128/jvi.71.5.4042-4054.1997

Endocytosis and recycling of varicella-zoster virus Fc receptor glycoprotein gE: internalization mediated by a YXXL motif in the cytoplasmic tail.

J K Olson 1, C Grose 1
PMCID: PMC191557  PMID: 9094682

Abstract

Varicella-zoster virus (VZV) encodes a cell surface Fc receptor, glycoprotein gE. VZV gE has previously been shown to display several features common to nonviral cell surface receptors. Most recently, VZV gE was reported to be tyrosine phosphorylated on a dimeric form (J. K. Olson, G. A. Bishop, and C. Grose, J. Virol. 71:110-119, 1997). Thereafter, attention focused on the ability of VZV gE to undergo receptor-mediated endocytosis. The current transient transfection studies demonstrated by confocal microscopy and internalization assays that VZV gE was endocytosed when expressed in HeLa cells. Endocytosis of gE was shown to be dependent on clathrin-coated vesicle formation within the cells. Subsequent colocalization studies showed that endocytosis of VZV gE closely mimicked endocytosis of the transferrin receptor. The gE cytoplasmic tail and more specifically tyrosine residue 582 were determined by mutagenesis studies to be important for efficient internalization of the protein; this tyrosine residue is part of a conserved YXXL motif. The amount of gE internalized at any given time reached a steady state of 32%. In addition, like the transferrin receptor, internalized gE recycled to the cell surface. The finding of gE endocytosis provided insight into earlier documentation of gE serine/threonine and tyrosine phosphorylation, since these phosphorylation events may serve as sorting signals for internalized receptors. Taken together with the previous discovery that both human and simian immunodeficiency virus envelope proteins can undergo endocytosis, the gE findings suggest that endocytosis of envelope components may be a posttranslational regulatory mechanism among divergent families of enveloped viruses.

Full Text

The Full Text of this article is available as a PDF (744.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ashworth R., Yu R., Nelson E. J., Dermer S., Gershengorn M. C., Hinkle P. M. Visualization of the thyrotropin-releasing hormone receptor and its ligand during endocytosis and recycling. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):512–516. doi: 10.1073/pnas.92.2.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bretscher M. S., Thomson J. N., Pearse B. M. Coated pits act as molecular filters. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4156–4159. doi: 10.1073/pnas.77.7.4156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Card J. P., Enquist L. W. Neurovirulence of pseudorabies virus. Crit Rev Neurobiol. 1995;9(2-3):137–162. [PubMed] [Google Scholar]
  4. Collawn J. F., Kuhn L. A., Liu L. F., Tainer J. A., Trowbridge I. S. Transplanted LDL and mannose-6-phosphate receptor internalization signals promote high-efficiency endocytosis of the transferrin receptor. EMBO J. 1991 Nov;10(11):3247–3253. doi: 10.1002/j.1460-2075.1991.tb04888.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collawn J. F., Stangel M., Kuhn L. A., Esekogwu V., Jing S. Q., Trowbridge I. S., Tainer J. A. Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell. 1990 Nov 30;63(5):1061–1072. doi: 10.1016/0092-8674(90)90509-d. [DOI] [PubMed] [Google Scholar]
  6. Davis C. G., Lehrman M. A., Russell D. W., Anderson R. G., Brown M. S., Goldstein J. L. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell. 1986 Apr 11;45(1):15–24. doi: 10.1016/0092-8674(86)90533-7. [DOI] [PubMed] [Google Scholar]
  7. Davis C. G., van Driel I. R., Russell D. W., Brown M. S., Goldstein J. L. The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis. J Biol Chem. 1987 Mar 25;262(9):4075–4082. [PubMed] [Google Scholar]
  8. Davison A. J., Scott J. E. The complete DNA sequence of varicella-zoster virus. J Gen Virol. 1986 Sep;67(Pt 9):1759–1816. doi: 10.1099/0022-1317-67-9-1759. [DOI] [PubMed] [Google Scholar]
  9. De Camilli P. The eighth Datta Lecture. Molecular mechanisms in synaptic vesicle recycling. FEBS Lett. 1995 Aug 1;369(1):3–12. doi: 10.1016/0014-5793(95)00739-v. [DOI] [PubMed] [Google Scholar]
  10. Dingwell K. S., Doering L. C., Johnson D. C. Glycoproteins E and I facilitate neuron-to-neuron spread of herpes simplex virus. J Virol. 1995 Nov;69(11):7087–7098. doi: 10.1128/jvi.69.11.7087-7098.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Egan M. A., Carruth L. M., Rowell J. F., Yu X., Siliciano R. F. Human immunodeficiency virus type 1 envelope protein endocytosis mediated by a highly conserved intrinsic internalization signal in the cytoplasmic domain of gp41 is suppressed in the presence of the Pr55gag precursor protein. J Virol. 1996 Oct;70(10):6547–6556. doi: 10.1128/jvi.70.10.6547-6556.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ghazizadeh S., Fleit H. B. Tyrosine phosphorylation provides an obligatory early signal for Fc gamma RII-mediated endocytosis in the monocytic cell line THP-1. J Immunol. 1994 Jan 1;152(1):30–41. [PubMed] [Google Scholar]
  13. Ghosh R. N., Gelman D. L., Maxfield F. R. Quantification of low density lipoprotein and transferrin endocytic sorting HEp2 cells using confocal microscopy. J Cell Sci. 1994 Aug;107(Pt 8):2177–2189. doi: 10.1242/jcs.107.8.2177. [DOI] [PubMed] [Google Scholar]
  14. Ghosh R. N., Maxfield F. R. Evidence for nonvectorial, retrograde transferrin trafficking in the early endosomes of HEp2 cells. J Cell Biol. 1995 Feb;128(4):549–561. doi: 10.1083/jcb.128.4.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldstein J. L., Brown M. S., Anderson R. G., Russell D. W., Schneider W. J. Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol. 1985;1:1–39. doi: 10.1146/annurev.cb.01.110185.000245. [DOI] [PubMed] [Google Scholar]
  16. Grose C. Glycoproteins encoded by varicella-zoster virus: biosynthesis, phosphorylation, and intracellular trafficking. Annu Rev Microbiol. 1990;44:59–80. doi: 10.1146/annurev.mi.44.100190.000423. [DOI] [PubMed] [Google Scholar]
  17. Harson R., Grose C. Egress of varicella-zoster virus from the melanoma cell: a tropism for the melanocyte. J Virol. 1995 Aug;69(8):4994–5010. doi: 10.1128/jvi.69.8.4994-5010.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hatfield C., Duus K. M., Chen J., Jones D. H., Grose C. Epitope mapping and tagging by recombination PCR mutagenesis. Biotechniques. 1997 Feb;22(2):332–337. doi: 10.2144/97222rr02. [DOI] [PubMed] [Google Scholar]
  19. Hathaway G. M., Traugh J. A. Casein kinases--multipotential protein kinases. Curr Top Cell Regul. 1982;21:101–127. [PubMed] [Google Scholar]
  20. Kishimoto A., Brown M. S., Slaughter C. A., Goldstein J. L. Phosphorylation of serine 833 in cytoplasmic domain of low density lipoprotein receptor by a high molecular weight enzyme resembling casein kinase II. J Biol Chem. 1987 Jan 25;262(3):1344–1351. [PubMed] [Google Scholar]
  21. LaBranche C. C., Sauter M. M., Haggarty B. S., Vance P. J., Romano J., Hart T. K., Bugelski P. J., Marsh M., Hoxie J. A. A single amino acid change in the cytoplasmic domain of the simian immunodeficiency virus transmembrane molecule increases envelope glycoprotein expression on infected cells. J Virol. 1995 Sep;69(9):5217–5227. doi: 10.1128/jvi.69.9.5217-5227.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lazarovits J., Roth M. A single amino acid change in the cytoplasmic domain allows the influenza virus hemagglutinin to be endocytosed through coated pits. Cell. 1988 Jun 3;53(5):743–752. doi: 10.1016/0092-8674(88)90092-x. [DOI] [PubMed] [Google Scholar]
  23. Lehrman M. A., Goldstein J. L., Brown M. S., Russell D. W., Schneider W. J. Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain. Cell. 1985 Jul;41(3):735–743. doi: 10.1016/s0092-8674(85)80054-4. [DOI] [PubMed] [Google Scholar]
  24. Litwin V., Jackson W., Grose C. Receptor properties of two varicella-zoster virus glycoproteins, gpI and gpIV, homologous to herpes simplex virus gE and gI. J Virol. 1992 Jun;66(6):3643–3651. doi: 10.1128/jvi.66.6.3643-3651.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Litwin V., Sandor M., Grose C. Cell surface expression of the varicella-zoster virus glycoproteins and Fc receptor. Virology. 1990 Sep;178(1):263–272. doi: 10.1016/0042-6822(90)90402-d. [DOI] [PubMed] [Google Scholar]
  26. Mauxion F., Le Borgne R., Munier-Lehmann H., Hoflack B. A casein kinase II phosphorylation site in the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor determines the high affinity interaction of the AP-1 Golgi assembly proteins with membranes. J Biol Chem. 1996 Jan 26;271(4):2171–2178. doi: 10.1074/jbc.271.4.2171. [DOI] [PubMed] [Google Scholar]
  27. McClain D. A., Maegawa H., Lee J., Dull T. J., Ulrich A., Olefsky J. M. A mutant insulin receptor with defective tyrosine kinase displays no biologic activity and does not undergo endocytosis. J Biol Chem. 1987 Oct 25;262(30):14663–14671. [PubMed] [Google Scholar]
  28. McGeoch D. J., Cook S., Dolan A., Jamieson F. E., Telford E. A. Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. J Mol Biol. 1995 Mar 31;247(3):443–458. doi: 10.1006/jmbi.1995.0152. [DOI] [PubMed] [Google Scholar]
  29. Montalvo E. A., Parmley R. T., Grose C. Structural analysis of the varicella-zoster virus gp98-gp62 complex: posttranslational addition of N-linked and O-linked oligosaccharide moieties. J Virol. 1985 Mar;53(3):761–770. doi: 10.1128/jvi.53.3.761-770.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Moss B., Elroy-Stein O., Mizukami T., Alexander W. A., Fuerst T. R. Product review. New mammalian expression vectors. Nature. 1990 Nov 1;348(6296):91–92. doi: 10.1038/348091a0. [DOI] [PubMed] [Google Scholar]
  31. Mostov K. E., de Bruyn Kops A., Deitcher D. L. Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis. Cell. 1986 Nov 7;47(3):359–364. doi: 10.1016/0092-8674(86)90592-1. [DOI] [PubMed] [Google Scholar]
  32. Mostov K. E., de Bruyn Kops A., Deitcher D. L. Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis. Cell. 1986 Nov 7;47(3):359–364. doi: 10.1016/0092-8674(86)90592-1. [DOI] [PubMed] [Google Scholar]
  33. Ohno H., Stewart J., Fournier M. C., Bosshart H., Rhee I., Miyatake S., Saito T., Gallusser A., Kirchhausen T., Bonifacino J. S. Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science. 1995 Sep 29;269(5232):1872–1875. doi: 10.1126/science.7569928. [DOI] [PubMed] [Google Scholar]
  34. Olson J. K., Bishop G. A., Grose C. Varicella-zoster virus Fc receptor gE glycoprotein: serine/threonine and tyrosine phosphorylation of monomeric and dimeric forms. J Virol. 1997 Jan;71(1):110–119. doi: 10.1128/jvi.71.1.110-119.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roth M. G., Doyle C., Sambrook J., Gething M. J. Heterologous transmembrane and cytoplasmic domains direct functional chimeric influenza virus hemagglutinins into the endocytic pathway. J Cell Biol. 1986 Apr;102(4):1271–1283. doi: 10.1083/jcb.102.4.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rothenberger S., Iacopetta B. J., Kühn L. C. Endocytosis of the transferrin receptor requires the cytoplasmic domain but not its phosphorylation site. Cell. 1987 May 8;49(3):423–431. doi: 10.1016/0092-8674(87)90295-9. [DOI] [PubMed] [Google Scholar]
  37. Rowell J. F., Stanhope P. E., Siliciano R. F. Endocytosis of endogenously synthesized HIV-1 envelope protein. Mechanism and role in processing for association with class II MHC. J Immunol. 1995 Jul 1;155(1):473–488. [PubMed] [Google Scholar]
  38. Sandoval I. V., Bakke O. Targeting of membrane proteins to endosomes and lysosomes. Trends Cell Biol. 1994 Aug;4(8):292–297. doi: 10.1016/0962-8924(94)90220-8. [DOI] [PubMed] [Google Scholar]
  39. Sauter M. M., Pelchen-Matthews A., Bron R., Marsh M., LaBranche C. C., Vance P. J., Romano J., Haggarty B. S., Hart T. K., Lee W. M. An internalization signal in the simian immunodeficiency virus transmembrane protein cytoplasmic domain modulates expression of envelope glycoproteins on the cell surface. J Cell Biol. 1996 Mar;132(5):795–811. doi: 10.1083/jcb.132.5.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schmid S. L. The mechanism of receptor-mediated endocytosis: more questions than answers. Bioessays. 1992 Sep;14(9):589–596. doi: 10.1002/bies.950140903. [DOI] [PubMed] [Google Scholar]
  41. Schwartz A. L. Receptor cell biology: receptor-mediated endocytosis. Pediatr Res. 1995 Dec;38(6):835–843. doi: 10.1203/00006450-199512000-00003. [DOI] [PubMed] [Google Scholar]
  42. Smith C. A., Davis T., Anderson D., Solam L., Beckmann M. P., Jerzy R., Dower S. K., Cosman D., Goodwin R. G. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990 May 25;248(4958):1019–1023. doi: 10.1126/science.2160731. [DOI] [PubMed] [Google Scholar]
  43. Stoorvogel W., Oorschot V., Geuze H. J. A novel class of clathrin-coated vesicles budding from endosomes. J Cell Biol. 1996 Jan;132(1-2):21–33. doi: 10.1083/jcb.132.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Trowbridge I. S., Collawn J. F., Hopkins C. R. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol. 1993;9:129–161. doi: 10.1146/annurev.cb.09.110193.001021. [DOI] [PubMed] [Google Scholar]
  45. Trowbridge I. S. Endocytosis and signals for internalization. Curr Opin Cell Biol. 1991 Aug;3(4):634–641. doi: 10.1016/0955-0674(91)90034-v. [DOI] [PubMed] [Google Scholar]
  46. White S., Taetle R., Seligman P. A., Rutherford M., Trowbridge I. S. Combinations of anti-transferrin receptor monoclonal antibodies inhibit human tumor cell growth in vitro and in vivo: evidence for synergistic antiproliferative effects. Cancer Res. 1990 Oct 1;50(19):6295–6301. [PubMed] [Google Scholar]
  47. Wileman T., Harding C., Stahl P. Receptor-mediated endocytosis. Biochem J. 1985 Nov 15;232(1):1–14. doi: 10.1042/bj2320001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yao Z., Jackson W., Grose C. Identification of the phosphorylation sequence in the cytoplasmic tail of the varicella-zoster virus Fc receptor glycoprotein gpI. J Virol. 1993 Aug;67(8):4464–4473. doi: 10.1128/jvi.67.8.4464-4473.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yao Z., Jones D. H., Grose C. Site-directed mutagenesis of herpesvirus glycoprotein phosphorylation sites by recombination polymerase chain reaction. PCR Methods Appl. 1992 Feb;1(3):205–207. doi: 10.1101/gr.1.3.205. [DOI] [PubMed] [Google Scholar]
  50. Zhu Z., Hao Y., Gershon M. D., Ambron R. T., Gershon A. A. Targeting of glycoprotein I (gE) of varicella-zoster virus to the trans-Golgi network by an AYRV sequence and an acidic amino acid-rich patch in the cytosolic domain of the molecule. J Virol. 1996 Oct;70(10):6563–6575. doi: 10.1128/jvi.70.10.6563-6575.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES