1887

Abstract

The herpesvirus regulatory protein IE110k possesses a cysteine-rich, RING finger motif required for its role in transactivation and virus replication. IE110k also localizes to subnuclear compartments termed PODs (PML oncogenic domains). Localization to PODs induces redistribution of the proteins associated with this nuclear compartment, including the cellular RING finger protein, PML. Here we construct a series of deletions, RING domain swaps and point mutations to analyse specific requirements within the IE110k RING finger for subnuclear localization, redistribution of PML and transactivation and we examine the relationship between these activities. We find that IE110k localizes to distinct nuclear subdomains that are more numerous than the cellular PODs and that mutation of two residues within a predicted loop of the RING finger, or replacing the IE110k RING finger with a RING finger from a cellular gene abrogates the ability of IE110k to localize to these extra compartments and traps IE110k in the original PODs. We further demonstrate that RING fingers from the cellular genes mdm-2 and Bmi I, when placed within IE110k, alter the nuclear distribution of IE110k, do not transactivate, and do not redistribute PML. We also demonstrate that the majority of wild-type IE110k, like PML, is associated with the nuclear matrix. Although substitutions and deletions within the RING finger abolish transactivation, these mutant proteins remain tightly associated with the matrix. These results further dissect the determinants involved in different aspects of nuclear compartmentalization of IE110k and are discussed in relation to PML, PODs and the IE110k RING finger.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-79-3-537
1998-03-01
2022-01-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/79/3/9519832.html?itemId=/content/journal/jgv/10.1099/0022-1317-79-3-537&mimeType=html&fmt=ahah

References

  1. Ahn J. H., Hayward G. S. 1997; The major immediate-early proteins IE1 and IE2 of human cytomegalovirus colocalise with and disrupt PML- associated nuclear bodies at very early times in infected permissive cells. Journal of Virology 71:4599–4613
    [Google Scholar]
  2. Ascoli C. A., Maul G. G. 1991; Identification of a novel nuclear domain. Journal of Cell Biology 112:785–795
    [Google Scholar]
  3. Barlow P. N., Luisi B., Milner A., Elliott M., Everett R. 1994; Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger. Journal of Molecular Biology 237:201–211
    [Google Scholar]
  4. Batchelor A. H., O’Hare P. 1992; Localization ofcis-acting sequence requirements in the promoter of the latency-associated transcript of herpes simplex virus type 1 required for cell-type-specific activity. Journal of Virology 66:3573–3582
    [Google Scholar]
  5. Boddy M. N., Freemont P. S., Borden K. L. 1994; The p53- associated protein MDM2 contains a newly characterized zinc-binding domain called the RING finger. Trends in Biochemical Science 19:198–199
    [Google Scholar]
  6. Boddy M. N., Howe K., Etkin L. D., Solomon E., Freemont P. S. 1996; PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13:971–982
    [Google Scholar]
  7. Cai W., Astor T. L., Liptak L. M., Cho C., Coen D. M., Schaffer P. A. 1993; The herpes simplex virus type 1 regulatory protein ICP0 enhances virus replication during acute infection and reactivation from latency. Journal of Virology 67:7501–7512
    [Google Scholar]
  8. Capco D. G., Wan K. M., Penman S. 1982; The nuclear matrix: three-dimensional architecture and protein composition. Cell 29:847–856
    [Google Scholar]
  9. Carvalho T., Seeler J.-S., Ohman K., Jordan P., Pettersson U., Akusjarvi G., Carmo-Fonseca M., Dejean A. 1995; Targeting of adenovirus ElA and E4-ORF3 proteins to nuclear matrix-associated PML bodies. Journal of Cell Biology 131:45–56
    [Google Scholar]
  10. Chang K.-S., Fan Y.-H., Andreff M., Liu J., Mu Z.-M. 1995; The PML gene encodes a phosphoprotein associated with the nuclear matrix. Blood 85:3646–3653
    [Google Scholar]
  11. Chen J. X., Zhu X. X., Silverstein S. 1991; Mutational analysis of the sequence encoding ICP0 from herpes simplex virus type l. Virology 180:207–220
    [Google Scholar]
  12. Clements G. B., Stow N. D. 1989; A herpes simplex virus type l mutant containing a deletion within immediate early gene l is latency- competent in mice. Journal of General Virology 70:2501–2506
    [Google Scholar]
  13. Doucas V., Ishov A. M., Romo A., Juguilon H., Weitzman M. D., Evans R. M., Maul G. G. 1996; Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes Development 10:196–207
    [Google Scholar]
  14. Dyck J. A., Maul G. G., Miller W. J., Chen J. D., Kakizuka A., Evans R. M. 1994; A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76:333–343
    [Google Scholar]
  15. Elliott G., Mouzakitis G., O’Hare P. 1995; VP16 interacts via its activation domain with VP22, a tegument protein of herpes simplex virus, and is relocated to a novel macromolecular assembly in coexpressing cells. Journal of Virology 69:7932–7941
    [Google Scholar]
  16. Everett R. D. 1986; The products of herpes simplex virus type 1 (HSV-1) immediate early genes 1, 2 and 3 can activate HSV-1 gene expression in trans . Journal of General Virology 67:2507–2513
    [Google Scholar]
  17. Everett R. D. 1987; A detailed mutational analysis of Vmw110, a trans-acting transcriptional activator encoded by herpes simplex virus type 1. EMBO Journal 6:2069–2076
    [Google Scholar]
  18. Everett R. D. 1988; Analysis of the functional domains of herpes simplex virus type 1 immediate-early polypeptide Vmw110. Journal of Molecular Biology 202:87–96
    [Google Scholar]
  19. Everett R. D., Maul G. G. 1994; HSV-1 IE protein Vmw110 causes redistribution of PML. EMBO Journal 13:5062–5069
    [Google Scholar]
  20. Everett R., Preston C., Stow N. 1991; Functional and genetic analysis of the role of Vmw110 in herpes simplex virus replication. In Herpesvirus Transcription and its Regulation pp 49–76 Wagner E. Edited by Boca Raton: CRC Press;
    [Google Scholar]
  21. Everett R. D., Barlow P., Milner A., Luisi B., Orr A., Hope G., Lyon D. 1993; A novel arrangement of zinc-binding residues and secondary structure in the C3HC4 motif of an alpha herpes virus protein family. Journal of Molecular Biology 234:1038–1047
    [Google Scholar]
  22. Everett R., Orr A., Elliott M. 1995a; The equine herpesvirus 1 gene 63 RING finger protein partially complements Vmw110, its herpes simplex virus type 1 counterpart. Journal of General Virology 76:2369–2374
    [Google Scholar]
  23. Everett R. D., Maul G. G., Orr A., Elliott M. 1995b; The cellular RING finger protein PML is not a functional counterpart of the herpes simplex virus type 1 RING finger protein Vmw110. Journal of General Virology 76:791–798
    [Google Scholar]
  24. Everett R., O’Hare P., O’Rourke D., Barlow P., Orr A. 1995c; Point mutations in the herpes simplex virus type 1 Vmw110 Ring finger helix affect activation of gene expression, viral growth, and interaction with PML-containing nuclear structures. Journal of Virology 69:7339–7344
    [Google Scholar]
  25. Everett R. D., Meredith M., Orr A., Cross A., Kathoria M., Parkinson J. 1997; A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO Journal 16:566–577
    [Google Scholar]
  26. Freemont P. S. 1993; The RING finger. A novel protein sequence motif related to the zinc finger. Annals of the New York Academy of Science 684:174–192
    [Google Scholar]
  27. Freemont P. S., Hanson I. M., Trowsdale J. 1991; A novel cysteine-rich sequence motif [letter]. Cell 64:483–484
    [Google Scholar]
  28. Gelman I. H., Silverstein S. 1985; Identification of immediate early genes from herpes simplex virus that transactivate the virus thymidine kinase gene. Proceedings of the National Academy of Sciences, USA 82:5265–5269
    [Google Scholar]
  29. Gelman I. H., Silverstein S. 1986; Co-ordinate regulation of herpes simplex virus gene expression is mediated by the functional interaction of two immediate early gene products. Journal of Molecular Biology 191:395–409
    [Google Scholar]
  30. Goddard A. D., Borrow J., Freemont P. S., Solomon E. 1991; Characterization of a zinc finger gene disrupted by the t(15; 17) in acute promyelocytic leukemia. Science 254:1371–1374
    [Google Scholar]
  31. Haupt Y., Alexander W. S., Barri G., Klinken S. P., Adams J. M. 1991; Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice [see comments]. Cell 65:753–763
    [Google Scholar]
  32. Kakizuka A., Miller W. H. Jr Umesono K., Warrell R. P. Jr Frankel S. R., Murty V. V., Dmitrovsky E., Evans R. M. 1991; Chromosomal translocation t(15 ;17)in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66:663–674
    [Google Scholar]
  33. Kelly C., Van Driel R., Wilkinson G. W. G. 1995; Disruption of PML-associated nuclear bodies during human cytomegalovirus infection. Journal of General Virology 76:2887–2893
    [Google Scholar]
  34. Knipe D. M., Smith J. L. 1986; A mutant herpesvirus protein leads to a block in nuclear localisation of other viral proteins. Molecular and Cellular Biology 6:276–284
    [Google Scholar]
  35. Koken M. H., Puvion-Dutilleul F., Guillemin M. C., Viron A., Linares C. G., Stuurman N., de Jong L., Szostecki C., Calvo F., Chomienne C., Degos L., Puvion E., de Thé H. 1994; The t(15; 17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO Journal 13:1073–1083
    [Google Scholar]
  36. Koriath F., Maul G. G., Plachter B., Staminger T., Ferry J. 1996; The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1. Experimental Cell Research 229:155–158
    [Google Scholar]
  37. Krappa R., Knebel M. D. 1991; Identification of the very early transcribed baculovirus gene PE-38. Journal of Virology 65:805–812
    [Google Scholar]
  38. Leib D. A., Coen D. M., Bogard C. L., Hicks K. A., Yager D. R., Knipe D. M., Tyler K. L., Schaffer P. A. 1989; Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. Journal of Virology 63:759–768
    [Google Scholar]
  39. Maul G. G., Guldner H. H., Spivack J. G. 1993; Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). Journal of General Virology 74:2679–2690
    [Google Scholar]
  40. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. 1992; The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245
    [Google Scholar]
  41. Moriuchi H., Moriuchi M., Cohen J. I. 1994; The RING finger domain of varicella zoster virus open reading frame 61 protein is required for its transregulatory functions. Virology 205:238–246
    [Google Scholar]
  42. Mullen M. A., Ciufo D. M., Hayward G. S. 1994; Mapping of intracellular localization domains and evidence for colocalization interactions between the IE110 and IE175 nuclear transactivator proteins of herpes simplex virus. Journal of Virology 68:3250–3266
    [Google Scholar]
  43. O’Hare P., Goding C. R. 1988; Herpes simplex virus regulatory elements and the immunoglobulin octamer domain bind a common factor and are both targets for virion transactivation. Cell 52:435–445
    [Google Scholar]
  44. O’Hare P., Hayward G. S. 1985; Evidence for a direct role for both the 175 000- and 110 000-molecular-weight immediate-early proteins of herpes simplex virus in the transactivation of delayed-early promoters. Journal of Virology 53:751–760
    [Google Scholar]
  45. O’Hare P., Mosca J., Hayward G. S. 1986; Multiple trans-acting proteins of herpes simplex virus that have different target promoter specificities and exhibit both positive and negative regulatory functions. Cancer Cells 4:175–189
    [Google Scholar]
  46. Pandolfi P. P., Grignani F., Alcalay M., Mencarelli A., Biondi A., LoCoco F., Grignani F., Pelicci P. G. 1991; Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6:1285–1292
    [Google Scholar]
  47. Puvion-Dutilleul F., ChelbiAlix M. K., Koken M., Quignon F., Puvion E., de Thé H. 1995; Adenovirus infection induces rearrangements in the intranuclear distribution of the nuclear body-associated PML protein. Experimental Cell Research 218:9–16
    [Google Scholar]
  48. Sacks W. R., Schaffer P. A. 1987; Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture. Journal of Virology 61:829–839
    [Google Scholar]
  49. Stow N. D., Stow E. C. 1986; Isolation and characterization of a herpes simplex virus type 1 mutant containing a deletion within the gene encoding the immediate early polypeptide Vmw110. Journal of General Virology 67:2571–2585
    [Google Scholar]
  50. Stuurman N., de Graaf A., Floore A., Josso A., Humbel B., de Jong L., van Driel R. 1992; A monoclonal antibody recognizing nuclear matrix-associated nuclear bodies. Journal of Cell Science 101:773–784
    [Google Scholar]
  51. Szekely L., Pokrovskaja K., Jiang W.-Q., de Thé H., Ringertz N., Klein G. 1996; The Epstein-Barr virus-encoded nuclear antigen EBNA-5 accumulates in PML-containing bodies. Journal of Virology 70:2562–2568
    [Google Scholar]
  52. van Lohuizen M., Verbeek S., Scheijen B., Wientjens E., van der Gulden H., Berns A. 1991; Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65:737–752
    [Google Scholar]
  53. Weis K., Rambaud S., Lavau C., Jansen J., Carvalho T., Carmo-Fonseca M., Lamond A., Dejean A. 1994; Retinoic acid regulates aberrant localisation of PML-RAR alpha in acute promyelocytic leukaemia cells. Cell 76:345–356
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-79-3-537
Loading
/content/journal/jgv/10.1099/0022-1317-79-3-537
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error