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. 1997 Feb 3;16(3):566–577. doi: 10.1093/emboj/16.3.566

A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.

R D Everett 1, M Meredith 1, A Orr 1, A Cross 1, M Kathoria 1, J Parkinson 1
PMCID: PMC1169660  PMID: 9034339

Abstract

Herpes simplex virus type 1 immediate-early protein Vmw110 is a non-specific activator of gene expression and is required for efficient initiation of the viral lytic cycle. Since Vmw110-deficient viruses reactivate inefficiently in mouse latency models it has been suggested that Vmw110 plays a role in the balance between the latent and lytic states of the virus. The mechanisms by which Vmw110 achieves these functions are poorly understood. Vmw110 migrates to discrete nuclear structures (ND10) which contain the cellular PML protein, and in consequence PML and other constituent proteins are dispersed. In addition, Vmw110 binds to a cellular protein of approximately 135 kDa, and its interactions with the 135 kDa protein and ND10 contribute to its ability to stimulate gene expression and viral lytic growth. In this report we identify the 135 kDa protein as a novel member of the ubiquitin-specific protease family. The protease is distributed in the nucleus in a micropunctate pattern with a limited number of larger discrete foci, some of which co-localize with PML in ND10. At early times of virus infection, the presence of Vmw110 increases the proportion of ND10 which contain the ubiquitin-specific protease. These results identify a novel, transitory component of ND10 and implicate a previously uncharacterized ubiquitin-dependent pathway in the control of viral gene expression.

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Selected References

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

  1. Ascoli C. A., Maul G. G. Identification of a novel nuclear domain. J Cell Biol. 1991 Mar;112(5):785–795. doi: 10.1083/jcb.112.5.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bailly V., Lamb J., Sung P., Prakash S., Prakash L. Specific complex formation between yeast RAD6 and RAD18 proteins: a potential mechanism for targeting RAD6 ubiquitin-conjugating activity to DNA damage sites. Genes Dev. 1994 Apr 1;8(7):811–820. doi: 10.1101/gad.8.7.811. [DOI] [PubMed] [Google Scholar]
  3. Baker R. T., Board P. G. The human ubiquitin-52 amino acid fusion protein gene shares several structural features with mammalian ribosomal protein genes. Nucleic Acids Res. 1991 Mar 11;19(5):1035–1040. doi: 10.1093/nar/19.5.1035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baker R. T., Tobias J. W., Varshavsky A. Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP2 and UBP3, and functional analysis of the UBP gene family. J Biol Chem. 1992 Nov 15;267(32):23364–23375. [PubMed] [Google Scholar]
  5. Boddy M. N., Howe K., Etkin L. D., Solomon E., Freemont P. S. 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. 1996 Sep 5;13(5):971–982. [PubMed] [Google Scholar]
  6. Cai W., Astor T. L., Liptak L. M., Cho C., Coen D. M., Schaffer P. A. The herpes simplex virus type 1 regulatory protein ICP0 enhances virus replication during acute infection and reactivation from latency. J Virol. 1993 Dec;67(12):7501–7512. doi: 10.1128/jvi.67.12.7501-7512.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cai W., Schaffer P. A. A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1. J Virol. 1991 Aug;65(8):4078–4090. doi: 10.1128/jvi.65.8.4078-4090.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clements G. B., Stow N. D. A herpes simplex virus type 1 mutant containing a deletion within immediate early gene 1 is latency-competent in mice. J Gen Virol. 1989 Sep;70(Pt 9):2501–2506. doi: 10.1099/0022-1317-70-9-2501. [DOI] [PubMed] [Google Scholar]
  9. Doucas V., Ishov A. M., Romo A., Juguilon H., Weitzman M. D., Evans R. M., Maul G. G. Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes Dev. 1996 Jan 15;10(2):196–207. doi: 10.1101/gad.10.2.196. [DOI] [PubMed] [Google Scholar]
  10. Everett R. D. Construction and characterization of herpes simplex virus type 1 mutants with defined lesions in immediate early gene 1. J Gen Virol. 1989 May;70(Pt 5):1185–1202. doi: 10.1099/0022-1317-70-5-1185. [DOI] [PubMed] [Google Scholar]
  11. Everett R. D., Cross A., Orr A. A truncated form of herpes simplex virus type 1 immediate-early protein Vmw110 is expressed in a cell type dependent manner. Virology. 1993 Dec;197(2):751–756. doi: 10.1006/viro.1993.1651. [DOI] [PubMed] [Google Scholar]
  12. Everett R. D., Maul G. G. HSV-1 IE protein Vmw110 causes redistribution of PML. EMBO J. 1994 Nov 1;13(21):5062–5069. doi: 10.1002/j.1460-2075.1994.tb06835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goddard A. D., Borrow J., Freemont P. S., Solomon E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science. 1991 Nov 29;254(5036):1371–1374. doi: 10.1126/science.1720570. [DOI] [PubMed] [Google Scholar]
  14. Harris R. A., Everett R. D., Zhu X. X., Silverstein S., Preston C. M. Herpes simplex virus type 1 immediate-early protein Vmw110 reactivates latent herpes simplex virus type 2 in an in vitro latency system. J Virol. 1989 Aug;63(8):3513–3515. doi: 10.1128/jvi.63.8.3513-3515.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Huang Y., Baker R. T., Fischer-Vize J. A. Control of cell fate by a deubiquitinating enzyme encoded by the fat facets gene. Science. 1995 Dec 15;270(5243):1828–1831. doi: 10.1126/science.270.5243.1828. [DOI] [PubMed] [Google Scholar]
  16. Kakizuka A., Miller W. H., Jr, Umesono K., Warrell R. P., Jr, Frankel S. R., Murty V. V., Dmitrovsky E., Evans R. M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663–674. doi: 10.1016/0092-8674(91)90112-c. [DOI] [PubMed] [Google Scholar]
  17. Kastner P., Perez A., Lutz Y., Rochette-Egly C., Gaub M. P., Durand B., Lanotte M., Berger R., Chambon P. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 1992 Feb;11(2):629–642. doi: 10.1002/j.1460-2075.1992.tb05095.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leib D. A., Coen D. M., Bogard C. L., Hicks K. A., Yager D. R., Knipe D. M., Tyler K. L., Schaffer P. A. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J Virol. 1989 Feb;63(2):759–768. doi: 10.1128/jvi.63.2.759-768.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lennon G., Auffray C., Polymeropoulos M., Soares M. B. The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics. 1996 Apr 1;33(1):151–152. doi: 10.1006/geno.1996.0177. [DOI] [PubMed] [Google Scholar]
  20. Maul G. G., Ishov A. M., Everett R. D. Nuclear domain 10 as preexisting potential replication start sites of herpes simplex virus type-1. Virology. 1996 Mar 1;217(1):67–75. doi: 10.1006/viro.1996.0094. [DOI] [PubMed] [Google Scholar]
  21. McCarthy A. M., McMahan L., Schaffer P. A. Herpes simplex virus type 1 ICP27 deletion mutants exhibit altered patterns of transcription and are DNA deficient. J Virol. 1989 Jan;63(1):18–27. doi: 10.1128/jvi.63.1.18-27.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Meredith M., Orr A., Elliott M., Everett R. Separation of sequence requirements for HSV-1 Vmw110 multimerisation and interaction with a 135-kDa cellular protein. Virology. 1995 May 10;209(1):174–187. doi: 10.1006/viro.1995.1241. [DOI] [PubMed] [Google Scholar]
  23. Meredith M., Orr A., Everett R. Herpes simplex virus type 1 immediate-early protein Vmw110 binds strongly and specifically to a 135-kDa cellular protein. Virology. 1994 May 1;200(2):457–469. doi: 10.1006/viro.1994.1209. [DOI] [PubMed] [Google Scholar]
  24. Murray A. Cyclin ubiquitination: the destructive end of mitosis. Cell. 1995 Apr 21;81(2):149–152. doi: 10.1016/0092-8674(95)90322-4. [DOI] [PubMed] [Google Scholar]
  25. Pandolfi P. P., Alcalay M., Fagioli M., Zangrilli D., Mencarelli A., Diverio D., Biondi A., Lo Coco F., Rambaldi A., Grignani F. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J. 1992 Apr;11(4):1397–1407. doi: 10.1002/j.1460-2075.1992.tb05185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Papa F. R., Hochstrasser M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature. 1993 Nov 25;366(6453):313–319. doi: 10.1038/366313a0. [DOI] [PubMed] [Google Scholar]
  27. Phelan A., Carmo-Fonseca M., McLaughlan J., Lamond A. I., Clements J. B. A herpes simplex virus type 1 immediate-early gene product, IE63, regulates small nuclear ribonucleoprotein distribution. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9056–9060. doi: 10.1073/pnas.90.19.9056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Poffenberger K. L., Raichlen P. E., Herman R. C. In vitro characterization of a herpes simplex virus type 1 ICP22 deletion mutant. Virus Genes. 1993 Jun;7(2):171–186. doi: 10.1007/BF01702397. [DOI] [PubMed] [Google Scholar]
  29. Rodriguez J. M., Salas M. L., Viñuela E. Genes homologous to ubiquitin-conjugating proteins and eukaryotic transcription factor SII in African swine fever virus. Virology. 1992 Jan;186(1):40–52. doi: 10.1016/0042-6822(92)90059-x. [DOI] [PubMed] [Google Scholar]
  30. Sacks W. R., Schaffer P. A. Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture. J Virol. 1987 Mar;61(3):829–839. doi: 10.1128/jvi.61.3.829-839.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sandri-Goldin R. M., Mendoza G. E. A herpesvirus regulatory protein appears to act post-transcriptionally by affecting mRNA processing. Genes Dev. 1992 May;6(5):848–863. doi: 10.1101/gad.6.5.848. [DOI] [PubMed] [Google Scholar]
  32. Scheffner M., Huibregtse J. M., Vierstra R. D., Howley P. M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993 Nov 5;75(3):495–505. doi: 10.1016/0092-8674(93)90384-3. [DOI] [PubMed] [Google Scholar]
  33. Scherer D. C., Brockman J. A., Chen Z., Maniatis T., Ballard D. W. Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11259–11263. doi: 10.1073/pnas.92.24.11259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Smith C. A., Bates P., Rivera-Gonzalez R., Gu B., DeLuca N. A. ICP4, the major transcriptional regulatory protein of herpes simplex virus type 1, forms a tripartite complex with TATA-binding protein and TFIIB. J Virol. 1993 Aug;67(8):4676–4687. doi: 10.1128/jvi.67.8.4676-4687.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stow N. D., Stow E. C. Isolation and characterization of a herpes simplex virus type 1 mutant containing a deletion within the gene encoding the immediate early polypeptide Vmw110. J Gen Virol. 1986 Dec;67(Pt 12):2571–2585. doi: 10.1099/0022-1317-67-12-2571. [DOI] [PubMed] [Google Scholar]
  36. Weis K., Rambaud S., Lavau C., Jansen J., Carvalho T., Carmo-Fonseca M., Lamond A., Dejean A. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell. 1994 Jan 28;76(2):345–356. doi: 10.1016/0092-8674(94)90341-7. [DOI] [PubMed] [Google Scholar]
  37. Wilson A. C., LaMarco K., Peterson M. G., Herr W. The VP16 accessory protein HCF is a family of polypeptides processed from a large precursor protein. Cell. 1993 Jul 16;74(1):115–125. doi: 10.1016/0092-8674(93)90299-6. [DOI] [PubMed] [Google Scholar]
  38. Yaffe M. B., Beegen H., Eckert R. L. Biophysical characterization of involucrin reveals a molecule ideally suited to function as an intermolecular cross-bridge of the keratinocyte cornified envelope. J Biol Chem. 1992 Jun 15;267(17):12233–12238. [PubMed] [Google Scholar]
  39. Yao F., Schaffer P. A. An activity specified by the osteosarcoma line U2OS can substitute functionally for ICP0, a major regulatory protein of herpes simplex virus type 1. J Virol. 1995 Oct;69(10):6249–6258. doi: 10.1128/jvi.69.10.6249-6258.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yoshida H., Kitamura K., Tanaka K., Omura S., Miyazaki T., Hachiya T., Ohno R., Naoe T. Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. Cancer Res. 1996 Jul 1;56(13):2945–2948. [PubMed] [Google Scholar]
  41. Zhu X. X., Chen J. X., Young C. S., Silverstein S. Reactivation of latent herpes simplex virus by adenovirus recombinants encoding mutant IE-0 gene products. J Virol. 1990 Sep;64(9):4489–4498. doi: 10.1128/jvi.64.9.4489-4498.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zhu Y., Carroll M., Papa F. R., Hochstrasser M., D'Andrea A. D. DUB-1, a deubiquitinating enzyme with growth-suppressing activity. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3275–3279. doi: 10.1073/pnas.93.8.3275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. de Thé H., Lavau C., Marchio A., Chomienne C., Degos L., Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991 Aug 23;66(4):675–684. doi: 10.1016/0092-8674(91)90113-d. [DOI] [PubMed] [Google Scholar]

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