1887

Abstract

The multifunctional Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein latency-associated nuclear antigen 2 (LANA2) has a critical role in KSHV-induced B-cell malignancies. LANA2 increases the level of small ubiquitin-like modifier (SUMO)2-ubiquitin-modified PML and induces the disruption of PML oncogenic domains (PODs) by a process that requires a non-covalent SUMO interaction domain (SIM) in LANA2. We now demonstrate that LANA2 is covalently conjugated to SUMO1 and SUMO2 both and in latently KSHV-infected B-cells. We show that a LANA2 SIM mutant exhibits a slightly altered sumoylation pattern, which suggests that non-covalent SUMO interactions represent a mechanism for determining SUMO substrate recognition and modification. In addition, several lysine residues were mapped as SUMO conjugation sites. A sumoylation-deficient mutant shows impaired ability to induce disruption of PODs, which suggests that either directly bound or covalently conjugated SUMO moieties may act as a bridge for interaction between LANA2 and other SUMO-modified or SUMO-interacting proteins required for disruption of PODs.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.024984-0
2011-01-01
2019-11-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/1/188.html?itemId=/content/journal/jgv/10.1099/vir.0.024984-0&mimeType=html&fmt=ahah

References

  1. Adamson, A. L. & Kenney, S. ( 2001; ). Epstein–Barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies. J Virol 75, 2388–2399.[CrossRef]
    [Google Scholar]
  2. Boggio, R. & Chiocca, S. ( 2006; ). Viruses and sumoylation: recent highlights. Curr Opin Microbiol 9, 430–436.[CrossRef]
    [Google Scholar]
  3. Campagna, M., Herranz, D., Garcia, M. A., Marcos-Villar, L., Gonzalez-Santamaria, J., Gallego, P., Gutierrez, S., Collado, M., Serrano, M. & other authors ( 2010; ). SIRT1 stabilizes PML promoting its sumoylation. Cell Death Differ in press. doi: 10.1038/cdd.2010.77.
    [Google Scholar]
  4. Chakrabarti, S. R., Sood, R., Nandi, S. & Nucifora, G. ( 2000; ). Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent assembly into nuclear bodies. Proc Natl Acad Sci U S A 97, 13281–13285.[CrossRef]
    [Google Scholar]
  5. Chang, P. C., Izumiya, Y., Wu, C. Y., Fitzgerald, L. D., Campbell, M., Ellison, T. J., Lam, K. S., Luciw, P. A. & Kung, H. J. ( 2010; ). Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific. J Biol Chem 285, 5266–5273.[CrossRef]
    [Google Scholar]
  6. Desterro, J. M., Rodriguez, M. S. & Hay, R. T. ( 1998; ). SUMO-1 modification of IκBα inhibits NF-κB activation. Mol Cell 2, 233–239.[CrossRef]
    [Google Scholar]
  7. Eladad, S., Ye, T. Z., Hu, P., Leversha, M., Beresten, S., Matunis, M. J. & Ellis, N. A. ( 2005; ). Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Hum Mol Genet 14, 1351–1365.[CrossRef]
    [Google Scholar]
  8. Esteban, M., Garcia, M. A., Domingo-Gil, E., Arroyo, J., Nombela, C. & Rivas, C. ( 2003; ). The latency protein LANA2 from Kaposi's sarcoma-associated herpesvirus inhibits apoptosis induced by dsRNA-activated protein kinase but not RNase L activation. J Gen Virol 84, 1463–1470.[CrossRef]
    [Google Scholar]
  9. Gill, G. ( 2004; ). SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev 18, 2046–2059.[CrossRef]
    [Google Scholar]
  10. Hay, R. T. ( 2005; ). SUMO: a history of modification. Mol Cell 18, 1–12.[CrossRef]
    [Google Scholar]
  11. Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G. & Jentsch, S. ( 2002; ). RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141.[CrossRef]
    [Google Scholar]
  12. Johnson, E. S. ( 2004; ). Protein modification by SUMO. Annu Rev Biochem 73, 355–382.[CrossRef]
    [Google Scholar]
  13. Joo, C. H., Shin, Y. C., Gack, M., Wu, L., Levy, D. & Jung, J. U. ( 2007; ). Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi's sarcoma-associated herpesvirus viral IRF homolog vIRF3. J Virol 81, 8282–8292.[CrossRef]
    [Google Scholar]
  14. Kamitani, T., Kito, K., Nguyen, H. P., Wada, H., Fukuda-Kamitani, T. & Yeh, E. T. ( 1998; ). Identification of three major sentrinization sites in PML. J Biol Chem 273, 26675–26682.[CrossRef]
    [Google Scholar]
  15. Kerscher, O. ( 2007; ). SUMO junction–what's your function? New insights through SUMO-interacting motifs. EMBO Rep 8, 550–555.[CrossRef]
    [Google Scholar]
  16. Li, X., Luo, Y., Yu, L., Lin, Y., Luo, D., Zhang, H., He, Y., Kim, Y. O., Kim, Y. & other authors ( 2008; ). SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis. Cell Death Differ 15, 739–750.[CrossRef]
    [Google Scholar]
  17. Lin, X., Sun, B., Liang, M., Liang, Y. Y., Gast, A., Hildebrand, J., Brunicardi, F. C., Melchior, F. & Feng, X. H. ( 2003; ). Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding. Mol Cell 11, 1389–1396.[CrossRef]
    [Google Scholar]
  18. Lin, D. Y., Huang, Y. S., Jeng, J. C., Kuo, H. Y., Chang, C. C., Chao, T. T., Ho, C. C., Chen, Y. C., Lin, T. P. & other authors ( 2006; ). Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 24, 341–354.[CrossRef]
    [Google Scholar]
  19. Lubyova, B. & Pitha, P. M. ( 2000; ). Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors. J Virol 74, 8194–8201.[CrossRef]
    [Google Scholar]
  20. Marcos-Villar, L., Lopitz-Otsoa, F., Gallego, P., Munoz-Fontela, C., Gonzalez-Santamaria, J., Campagna, M., Shou-Jiang, G., Rodriguez, M. S. & Rivas, C. ( 2009; ). Kaposi's sarcoma-associated herpesvirus protein LANA2 disrupts PML oncogenic domains and inhibits PML-mediated transcriptional repression of the survivin gene. J Virol 83, 8849–8858.[CrossRef]
    [Google Scholar]
  21. Matunis, M. J., Zhang, X. D. & Ellis, N. A. ( 2006; ). SUMO: the glue that binds. Dev Cell 11, 596–597.[CrossRef]
    [Google Scholar]
  22. Meluh, P. B. & Koshland, D. ( 1995; ). Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol Biol Cell 6, 793–807.[CrossRef]
    [Google Scholar]
  23. Meulmeester, E. & Melchior, F. ( 2008; ). Cell biology: SUMO. Nature 452, 709–711.[CrossRef]
    [Google Scholar]
  24. Minty, A., Dumont, X., Kaghad, M. & Caput, D. ( 2000; ). Covalent modification of p73α by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J Biol Chem 275, 36316–36323.[CrossRef]
    [Google Scholar]
  25. Rivas, C., Thlick, A. E., Parravicini, C., Moore, P. S. & Chang, Y. ( 2001; ). Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J Virol 75, 429–438.[CrossRef]
    [Google Scholar]
  26. Rui, H. L., Fan, E., Zhou, H. M., Xu, Z., Zhang, Y. & Lin, S. C. ( 2002; ). SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J Biol Chem 277, 42981–42986.[CrossRef]
    [Google Scholar]
  27. Seo, T., Park, J., Lim, C. & Choe, J. ( 2004; ). Inhibition of nuclear factor κB activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus. Oncogene 23, 6146–6155.[CrossRef]
    [Google Scholar]
  28. Shin, Y. C., Joo, C. H., Gack, M. U., Lee, H. R. & Jung, J. U. ( 2008; ). Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression. Cancer Res 68, 1751–1759.[CrossRef]
    [Google Scholar]
  29. Suzuki, T., Ichiyama, A., Saitoh, H., Kawakami, T., Omata, M., Chung, C. H., Kimura, M., Shimbara, N. & Tanaka, K. ( 1999; ). A new 30-kDa ubiquitin-related SUMO-1 hydrolase from bovine brain. J Biol Chem 274, 31131–31134.[CrossRef]
    [Google Scholar]
  30. Takahashi, H., Hatakeyama, S., Saitoh, H. & Nakayama, K. I. ( 2005; ). Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein. J Biol Chem 280, 5611–5621.[CrossRef]
    [Google Scholar]
  31. Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H. & Hay, R. T. ( 2001; ). Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276, 35368–35374.[CrossRef]
    [Google Scholar]
  32. Ulrich, H. D. ( 2009; ). The SUMO system: an overview. Methods Mol Biol 497, 3–16.
    [Google Scholar]
  33. Vertegaal, A. C., Andersen, J. S., Ogg, S. C., Hay, R. T., Mann, M. & Lamond, A. I. ( 2006; ). Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol Cell Proteomics 5, 2298–2310.[CrossRef]
    [Google Scholar]
  34. Weger, S., Hammer, E. & Heilbronn, R. ( 2004; ). SUMO-1 modification regulates the protein stability of the large regulatory protein Rep78 of adeno associated virus type 2 (AAV-2). Virology 330, 284–294.[CrossRef]
    [Google Scholar]
  35. Wies, E., Mori, Y., Hahn, A., Kremmer, E., Sturzl, M., Fleckenstein, B. & Neipel, F. ( 2008; ). The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells. Blood 111, 320–327.[CrossRef]
    [Google Scholar]
  36. Zhao, J. ( 2007; ). Sumoylation regulates diverse biological processes. Cell Mol Life Sci 64, 3017–3033.[CrossRef]
    [Google Scholar]
  37. Zhu, J., Zhu, S., Guzzo, C. M., Ellis, N. A., Sung, K. S., Choi, C. Y. & Matunis, M. J. ( 2008; ). Small ubiquitin-related modifier (SUMO) binding determines substrate recognition and paralog-selective SUMO modification. J Biol Chem 283, 29405–29415.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.024984-0
Loading
/content/journal/jgv/10.1099/vir.0.024984-0
Loading

Data & Media loading...

Supplements

vol. , part 1, pp. 188–194.

Modification of PML by SUMO1 SUMO interaction domain contributes to SUMOylation in LANA2 LANA2 protein stability is unaffected by SUMOylation SUMO conjugation to LANA2 contributes to the degradation of haemagglutinin–PML Putative SUMO-binding domains for LANA2 Oligonucleotides for LANA2 mutagenesis



PDF

Most Cited This Month

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