1887

Journal of General Virology header logo

Volume 96, Issue 5

The ORF3 protein of porcine circovirus type 2 promotes secretion of IL-6 and IL-8 in porcine epithelial cells by facilitating proteasomal degradation of regulator of G protein signalling 16 through physical interaction Free

Abstract

Porcine circovirus type 2 (PCV2) is the main aetiological agent of postweaning multisystemic wasting syndrome. The mechanism of pathogenicity associated with PCV2 infection is still not fully understood. Nevertheless, the fact that large amounts of proinflammatory cytokines within lymphoid tissues are released during the early stage of PCV2 infection may induce chronic inflammatory responses followed by the destruction of lymphoid tissues. However, how PCV2 infection causes an excessive inflammatory response in the host immune system during the early stage of PCV2 infection has still not been elucidated. In this study, we show that direct interaction between the PCV2 ORF3 and regulator of G protein signalling 16 (RGS16) within the cytoplasm of host cells leads to ubiquitin-mediated proteasomal degradation of RGS16. Facilitated degradation of the RGS16 by PCV2 ORF3 further enhances NFκB translocation into the nucleus through the ERK1/2 signalling pathway and increased IL-6 and IL-8 mRNA transcripts. Consequently, more severe inflammatory responses and leukocyte infiltration occur around host cells. This evidence may be the first clue explaining the molecular basis of how excessive amounts of proinflammatory cytokines within lymphoid tissues are released during the early stage of PCV2 infection.

  • Received:
  • Accepted:
  • Published Online:
© 2015 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.000046
2015-05-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/5/1098.html?itemId=/content/journal/jgv/10.1099/vir.0.000046&mimeType=html&fmt=ahah

References

  1. Allan G. M., Ellis J. A. 2000; Porcine circoviruses: a review. J Vet Diagn Invest 12:3–14 [View Article][PubMed]
     [Google Scholar]
  2. Allan G. M., Kennedy S., McNeilly F., Foster J. C., Ellis J. A., Krakowka S. J., Meehan B. M., Adair B. M. 1999; Experimental reproduction of severe wasting disease by co-infection of pigs with porcine circovirus and porcine parvovirus. J Comp Pathol 121:1–11 [View Article][PubMed]
     [Google Scholar]
  3. Anger T., Klintworth N., Stumpf C., Daniel W. G., Mende U., Garlichs C. D. 2007; RGS protein specificity towards Gq- and Gi/o-mediated ERK 1/2 and Akt activation, in vitro. J Biochem Mol Biol 40:899–910 [View Article][PubMed]
     [Google Scholar]
  4. Baggiolini M., Clark-Lewis I. 1992; Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Lett 307:97–101 [View Article][PubMed]
     [Google Scholar]
  5. Baldwin A. S. Jr 1996; The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–681 [View Article][PubMed]
     [Google Scholar]
  6. Berman D. M., Gilman A. G. 1998; Mammalian RGS proteins: barbarians at the gate. J Biol Chem 273:1269–1272 [View Article][PubMed]
     [Google Scholar]
  7. Bonizzi G., Karin M. 2004; The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288 [View Article][PubMed]
     [Google Scholar]
  8. Chen C., Seow K. T., Guo K., Yaw L. P., Lin S. C. 1999; The membrane association domain of RGS16 contains unique amphipathic features that are conserved in RGS4 and RGS5. J Biol Chem 274:19799–19806 [View Article][PubMed]
     [Google Scholar]
  9. Cho H., Kehrl J. H. 2009; Regulation of immune function by G protein-coupled receptors, trimeric G proteins, and RGS proteins. Prog Mol Biol Translational Sci 86:249–298 [View Article][PubMed]
     [Google Scholar]
  10. Darwich L., Pié S., Rovira A., Segalés J., Domingo M., Oswald I. P., Mateu E. 2003; Cytokine mRNA expression profiles in lymphoid tissues of pigs naturally affected by postweaning multisystemic wasting syndrome. J Gen Virol 84:2117–2125 [View Article][PubMed]
     [Google Scholar]
  11. Dohlman H. G., Thorner J. 1997; RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem 272:3871–3874 [View Article][PubMed]
     [Google Scholar]
  12. Druey K. M. 2009; Regulation of G-protein-coupled signaling pathways in allergic inflammation. Immunol Res 43:62–76 [View Article][PubMed]
     [Google Scholar]
  13. Dvorak C. M. T., Puvanendiran S., Murtaugh M. P. 2013; Cellular pathogenesis of porcine circovirus type 2 infection. Virus Res 174:60–68 [View Article][PubMed]
     [Google Scholar]
  14. Fenaux M., Halbur P. G., Haqshenas G., Royer R., Thomas P., Nawagitgul P., Gill M., Toth T. E., Meng X. J. 2002; Cloned genomic DNA of type 2 porcine circovirus is infectious when injected directly into the liver and lymph nodes of pigs: characterization of clinical disease, virus distribution, and pathologic lesions. J Virol 76:541–551 [View Article][PubMed]
     [Google Scholar]
  15. He J., Cao J., Zhou N., Jin Y., Wu J., Zhou J. 2013; Identification and functional analysis of the novel ORF4 protein encoded by porcine circovirus type 2. J Virol 87:1420–1429 [View Article][PubMed]
     [Google Scholar]
  16. Hyun J. J., Chun H. J., Keum B., Seo Y. S., Kim Y. S., Jeen Y. T., Lee H. S., Um S. H., Kim C. D. et al. 2010; Effect of omeprazole on the expression of transcription factors in osteoclasts and osteoblasts. Int J Mol Med 26:877–883[PubMed]
     [Google Scholar]
  17. Kim E. M., Lee H. H., Kim S. H., Son Y. O., Lee S. J., Han J., Bae J., Kim S. J., Park C. G. et al. 2011; The mouse small ubiquitin-like modifier-2 (SUMO-2) inhibits interleukin-12 (IL-12) production in mature dendritic cells by blocking the translocation of the p65 subunit of NFκB into the nucleus. Mol Immunol 48:2189–2197 [View Article][PubMed]
     [Google Scholar]
  18. Lee J. H., Rho S. B., Park S. Y., Chun T. 2008; Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22. FEBS Lett 582:1210–1218 [View Article][PubMed]
     [Google Scholar]
  19. Liu J., Chen I., Kwang J. 2005; Characterization of a previously unidentified viral protein in porcine circovirus type 2-infected cells and its role in virus-induced apoptosis. J Virol 79:8262–8274 [View Article][PubMed]
     [Google Scholar]
  20. Liu J., Chen I., Du Q., Chua H., Kwang J. 2006; The ORF3 protein of porcine circovirus type 2 is involved in viral pathogenesis in vivo. J Virol 80:5065–5073 [View Article][PubMed]
     [Google Scholar]
  21. Liu J., Zhu Y., Chen I., Lau J., He F., Lau A., Wang Z., Karuppannan A. K., Kwang J. 2007; The ORF3 protein of porcine circovirus type 2 interacts with porcine ubiquitin E3 ligase Pirh2 and facilitates p53 expression in viral infection. J Virol 81:9560–9567 [View Article][PubMed]
     [Google Scholar]
  22. Mankertz A., Mankertz J., Wolf K., Buhk H. J. 1998; Identification of a protein essential for replication of porcine circovirus. J Gen Virol 79:381–384[PubMed] [CrossRef]
     [Google Scholar]
  23. Nawagitgul P., Morozov I., Bolin S. R., Harms P. A., Sorden S. D., Paul P. S. 2000; Open reading frame 2 of porcine circovirus type 2 encodes a major capsid protein. J Gen Virol 81:2281–2287[PubMed] [CrossRef]
     [Google Scholar]
  24. Opriessnig T., Meng X. J., Halbur P. G. 2007; Porcine circovirus type 2 associated disease: update on current terminology, clinical manifestations, pathogenesis, diagnosis, and intervention strategies. J Vet Diagn Invest 19:591–615 [View Article][PubMed]
     [Google Scholar]
  25. Proost P., Wuyts A., van Damme J. 1996; The role of chemokines in inflammation. Int J Clin Lab Res 26:211–223 [View Article][PubMed]
     [Google Scholar]
  26. Rodríguez-Arrioja G. M., Segalés J., Calsamiglia M., Resendes A. R., Balasch M., Plana-Duran J., Casal J., Domingo M. 2002; Dynamics of porcine circovirus type 2 infection in a herd of pigs with postweaning multisystemic wasting syndrome. Am J Vet Res 63:354–357 [View Article][PubMed]
     [Google Scholar]
  27. Segalés J., Allan G. M., Domingo M. 2005; Porcine circovirus diseases. Anim Health Res Rev 6:119–142 [View Article][PubMed]
     [Google Scholar]
  28. Segalés J., Kekarainen T., Cortey M. 2013; The natural history of porcine circovirus type 2: from an inoffensive virus to a devastating swine disease?. Vet Microbiol 165:13–20 [View Article][PubMed]
     [Google Scholar]
  29. Shankar S. P., Wilson M. S., DiVietro J. A., Mentink-Kane M. M., Xie Z., Wynn T. A., Druey K. M. 2012; RGS16 attenuates pulmonary Th2/Th17 inflammatory responses. J Immunol 188:6347–6356 [View Article][PubMed]
     [Google Scholar]
  30. Sroussi H. Y., Berline J., Palefsky J. M. 2007; Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro. J Leukoc Biol 81:818–824 [View Article][PubMed]
     [Google Scholar]
  31. Timmusk S., Fossum C., Berg M. 2006; Porcine circovirus type 2 replicase binds the capsid protein and an intermediate filament-like protein. J Gen Virol 87:3215–3223 [View Article][PubMed]
     [Google Scholar]
  32. Tischer I., Bode L., Peters D., Pociuli S., Germann B. 1995; Distribution of antibodies to porcine circovirus in swine populations of different breeding farms. Arch Virol 140:737–743 [View Article][PubMed]
     [Google Scholar]
  33. Vasilatos S. N., Katz T. A., Oesterreich S., Wan Y., Davidson N. E., Huang Y. 2013; Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis 34:1196–1207 [View Article][PubMed]
     [Google Scholar]
  34. Wang R., Nan Y., Yu Y., Zhang Y. J. 2013; Porcine reproductive and respiratory syndrome virus Nsp1β inhibits interferon-activated JAK/STAT signal transduction by inducing karyopherin-α1 degradation. J Virol 87:5219–5228 [View Article][PubMed]
     [Google Scholar]
  35. Wei L., Kwang J., Wang J., Shi L., Yang B., Li Y., Liu J. 2008; Porcine circovirus type 2 induces the activation of nuclear factor kappa B by IκBα degradation. Virology 378:177–184 [View Article][PubMed]
     [Google Scholar]
  36. Wittamer V., Bondue B., Guillabert A., Vassart G., Parmentier M., Communi D. 2005; Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity. J Immunol 175:487–493 [View Article][PubMed]
     [Google Scholar]
  37. Xie G. X., Palmer P. P. 2007; How regulators of G protein signaling achieve selective regulation. J Mol Biol 366:349–365 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.000046
Loading
The ORF3 protein of porcine circovirus type 2 promotes secretion of IL-6 and IL-8 in porcine epithelial cells by facilitating proteasomal degradation of regulator of G protein signalling 16 through physical interaction
J. Gen. Virol. 96, 1098 (2015); https://doi.org/10.1099/vir.0.000046
/content/journal/jgv/10.1099/vir.0.000046
/content/journal/jgv/10.1099/vir.0.000046
Loading

Data & Media loading...

Supplements

Supplementary Data

PDF

Most cited 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