1887

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a deubiquitinating enzyme, reportedly blocks poly I : C-induced activation of interferon regulatory factor 3 and nuclear factor kappa B, reducing interferon (IFN) induction. This study investigated type I IFN antagonist mechanism of PLpro in human promonocytes. PLpro antagonized IFN-α-induced responses such as interferon-stimulated response element- and AP-1-driven promoter activation, protein kinase R, 2′-5′-oligoadenylate synthetase (OAS), interleukin (IL)-6 and IL-8 expression, and signal transducers and activators of transcription (STAT) 1 (Tyr701), STAT1 (Ser727) and c-Jun phosphorylation. A proteomics approach demonstrated downregulation of extracellular signal-regulated kinase (ERK) 1 and upregulation of ubiquitin-conjugating enzyme (UBC) E2-25k as inhibitory mechanism of PLpro on IFN-α-induced responses. IFN-α treatment significantly induced mRNA expression of UBC E2-25k, but not ERK1, causing time-dependent decrease of ERK1, but not ERK2, in PLpro-expressing cells. Poly-ubiquitination of ERK1 showed a relationship between ERK1 and ubiquitin proteasome signalling pathways associated with IFN antagonism by PLpro. Combination treatment of IFN-α and the proteasome inhibitor MG-132 showed a time-dependent restoration of ERK1 protein levels and significant increase of ERK1, STAT1 and c-Jun phosphorylation in PLpro-expressing cells. Importantly, PD098059 (an ERK1/2 inhibitor) treatment significantly reduced IFN-α-induced ERK1 and STAT1 phosphorylation, inhibiting IFN-α-induced expression of 2′-5′-OAS in vector control cells and PLpro-expressing cells. Overall results proved downregulation of ERK1 by ubiquitin proteasomes and suppression of interaction between ERK1 and STAT1 as type I IFN antagonist function of SARS-CoV PLpro.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.028936-0
2011-05-01
2019-12-05
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/5/1127.html?itemId=/content/journal/jgv/10.1099/vir.0.028936-0&mimeType=html&fmt=ahah

References

  1. Aceves-Luquero C. I. , Agarwal A. , Callejas-Valera J. L. , Arias-González L. , Esparís-Ogando A. , del Peso Ovalle L. , Bellón-Echeverria I. , de la Cruz-Morcillo M. A. , Galán Moya E. M. et al. ( 2009; ). ERK2, but not ERK1, mediates acquired and “de novo” resistance to imatinib mesylate: implication for CML therapy. . PLoS ONE 4:, e6124. [CrossRef] [PubMed]
    [Google Scholar]
  2. Banninger G. , Reich N. C. . ( 2004; ). STAT2 nuclear trafficking. . J Biol Chem 279:, 39199–39206. [CrossRef] [PubMed]
    [Google Scholar]
  3. Barretto N. , Jukneliene D. , Ratia K. , Chen Z. , Mesecar A. D. , Baker S. C. . ( 2005; ). The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. . J Virol 79:, 15189–15198. [CrossRef] [PubMed]
    [Google Scholar]
  4. Biron C. A. . ( 2001; ). Interferons alpha and beta as immune regulators–a new look. . Immunity 14:, 661–664. [CrossRef] [PubMed]
    [Google Scholar]
  5. Caraglia M. , Tagliaferri P. , Marra M. , Giuberti G. , Budillon A. , Gennaro E. D. , Pepe S. , Vitale G. , Improta S. et al. ( 2003; ). EGF activates an inducible survival response via the RAS→Erk-1/2 pathway to counteract interferon-α-mediated apoptosis in epidermoid cancer cells. . Cell Death Differ 10:, 218–229. [CrossRef] [PubMed]
    [Google Scholar]
  6. Deb D. K. , Sassano A. , Lekmine F. , Majchrzak B. , Verma A. , Kambhampati S. , Uddin S. , Rahman A. , Fish E. N. , Platanias L. C. . ( 2003; ). Activation of protein kinase Cδ by IFN-γ. . J Immunol 171:, 267–273.[PubMed] [CrossRef]
    [Google Scholar]
  7. Devaraj S. G. , Wang N. , Chen Z. , Chen Z. , Tseng M. , Barretto N. , Lin R. , Peters C. J. , Tseng C. T. et al. ( 2007; ). Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. . J Biol Chem 282:, 32208–32221. [CrossRef] [PubMed]
    [Google Scholar]
  8. Frieman M. , Ratia K. , Johnston R. E. , Mesecar A. D. , Baric R. S. . ( 2009; ). Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-κB signaling. . J Virol 83:, 6689–6705. [CrossRef] [PubMed]
    [Google Scholar]
  9. Gedey R. , Jin X. L. , Hinthong O. , Shisler J. L. . ( 2006; ). Poxviral regulation of the host NF-κB response: the vaccinia virus M2L protein inhibits induction of NF-κB activation via an ERK2 pathway in virus-infected human embryonic kidney cells. . J Virol 80:, 8676–8685. [CrossRef] [PubMed]
    [Google Scholar]
  10. Giannakopoulos N. V. , Luo J. K. , Papov V. , Zou W. , Lenschow D. J. , Jacobs B. S. , Borden E. C. , Li J. , Virgin H. W. , Zhang D. E. . ( 2005; ). Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. . Biochem Biophys Res Commun 336:, 496–506. [CrossRef] [PubMed]
    [Google Scholar]
  11. He L. , Ding Y. , Zhang Q. , Che X. , He Y. , Shen H. , Wang H. , Li Z. , Zhao L. et al. ( 2006; ). Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. . J Pathol 210:, 288–297. [CrossRef] [PubMed]
    [Google Scholar]
  12. Hoffmann E. , Dittrich-Breiholz O. , Holtmann H. , Kracht M. . ( 2002; ). Multiple control of interleukin-8 gene expression. . J Leukoc Biol 72:, 847–855.[PubMed]
    [Google Scholar]
  13. Hsueh P. R. , Chen P. J. , Hsiao C. H. , Yeh S. H. , Cheng W. C. , Wang J. L. , Chiang B. L. , Chang S. C. , Chang F. Y. et al. ( 2004; ). Patient data, early SARS epidemic, Taiwan. . Emerg Infect Dis 10:, 489–493.[PubMed] [CrossRef]
    [Google Scholar]
  14. Huang K. J. , Su I. J. , Theron M. , Wu Y. C. , Lai S. K. , Liu C. C. , Lei H. Y. . ( 2005; ). An interferon-gamma-related cytokine storm in SARS patients. . J Med Virol 75:, 185–194. [CrossRef] [PubMed]
    [Google Scholar]
  15. Lai C. C. , Jou M. J. , Huang S. Y. , Li S. W. , Wan L. , Tsai F. J. , Lin C. W. . ( 2007; ). Proteomic analysis of up-regulated proteins in human promonocyte cells expressing severe acute respiratory syndrome coronavirus 3C-like protease. . Proteomics 7:, 1446–1460. [CrossRef] [PubMed]
    [Google Scholar]
  16. Laine A. , Ronai Z. . ( 2005; ). Ubiquitin chains in the ladder of MAPK signaling. . Sci STKE 2005:, re5. [CrossRef] [PubMed]
    [Google Scholar]
  17. Lee N. , Hui D. , Wu A. , Chan P. , Cameron P. , Joynt G. M. , Ahuja A. , Yung M. Y. , Leung C. B. et al. ( 2003; ). A major outbreak of severe acute respiratory syndrome in Hong Kong. . N Engl J Med 348:, 1986–1994. [CrossRef] [PubMed]
    [Google Scholar]
  18. Lin C. W. , Wu C. F. , Hsiao N. W. , Chang C. Y. , Li S. W. , Wan L. , Lin Y. J. , Lin W. Y. . ( 2008; ). Aloe-emodin is an interferon-inducing agent with antiviral activity against Japanese encephalitis virus and enterovirus 71. . Int J Antimicrob Agents 32:, 355–359. [CrossRef] [PubMed]
    [Google Scholar]
  19. Lindner H. A. , Fotouhi-Ardakani N. , Lytvyn V. , Lachance P. , Sulea T. , Ménard R. . ( 2005; ). The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. . J Virol 79:, 15199–15208. [CrossRef] [PubMed]
    [Google Scholar]
  20. Lombardi A. , Cantini G. , Piscitelli E. , Gelmini S. , Francalanci M. , Mello T. , Ceni E. , Varano G. , Forti G. et al. ( 2008; ). A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells. . Arterioscler Thromb Vasc Biol 28:, 718–724. [CrossRef] [PubMed]
    [Google Scholar]
  21. Lu Z. , Hunter T. . ( 2009; ). Degradation of activated protein kinases by ubiquitination. . Annu Rev Biochem 78:, 435–475. [CrossRef] [PubMed]
    [Google Scholar]
  22. Lu Z. , Xu S. , Joazeiro C. , Cobb M. H. , Hunter T. . ( 2002; ). The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. . Mol Cell 9:, 945–956. [CrossRef] [PubMed]
    [Google Scholar]
  23. Malakhov M. P. , Kim K. I. , Malakhova O. A. , Jacobs B. S. , Borden E. C. , Zhang D. E. . ( 2003; ). High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transduction. . J Biol Chem 278:, 16608–16613. [CrossRef] [PubMed]
    [Google Scholar]
  24. Marchi M. , D’Antoni A. , Formentini I. , Parra R. , Brambilla R. , Ratto G. M. , Costa M. . ( 2008; ). The N-terminal domain of ERK1 accounts for the functional differences with ERK2. . PLoS ONE 3:, e3873. [CrossRef] [PubMed]
    [Google Scholar]
  25. Marra M. A. , Jones S. J. , Astell C. R. , Holt R. A. , Brooks-Wilson A. , Butterfield Y. S. , Khattra J. , Asano J. K. , Barber S. A. et al. ( 2003; ). The genome sequence of the SARS-associated coronavirus. . Science 300:, 1399–1404. [CrossRef] [PubMed]
    [Google Scholar]
  26. Matsumoto S. , Hara T. , Hori T. , Mitsuyama K. , Nagaoka M. , Tomiyasu N. , Suzuki A. , Sata M. . ( 2005; ). Probiotic Lactobacillus-induced improvement in murine chronic inflammatory bowel disease is associated with the down-regulation of pro-inflammatory cytokines in lamina propria mononuclear cells. . Clin Exp Immunol 140:, 417–426. [CrossRef] [PubMed]
    [Google Scholar]
  27. Milella M. , Kornblau S. M. , Andreeff M. . ( 2003; ). The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies. . Rev Clin Exp Hematol 7:, 160–190.[PubMed]
    [Google Scholar]
  28. Nicholls J. M. , Poon L. L. , Lee K. C. , Ng W. F. , Lai S. T. , Leung C. Y. , Chu C. M. , Hui P. K. , Mak K. L. , Lim W. . ( 2003; ). Lung pathology of fatal severe acute respiratory syndrome. . Lancet 361:, 1773–1778. [CrossRef] [PubMed]
    [Google Scholar]
  29. Pagès G. , Pouysségur J. . ( 2004; ). Study of MAPK signaling using knockout mice. . Methods Mol Biol 250:, 155–166.[PubMed]
    [Google Scholar]
  30. Ratia K. , Saikatendu K. S. , Santarsiero B. D. , Barretto N. , Baker S. C. , Stevens R. C. , Mesecar A. D. . ( 2006; ). Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. . Proc Natl Acad Sci U S A 103:, 5717–5722. [CrossRef] [PubMed]
    [Google Scholar]
  31. Rota P. A. , Oberste M. S. , Monroe S. S. , Nix W. A. , Campagnoli R. , Icenogle J. P. , Peñaranda S. , Bankamp B. , Maher K. et al. ( 2003; ). Characterization of a novel coronavirus associated with severe acute respiratory syndrome. . Science 300:, 1394–1399. [CrossRef] [PubMed]
    [Google Scholar]
  32. Samuel C. E. . ( 2001; ). Antiviral actions of interferons. . Clin Microbiol Rev 14:, 778–809. [CrossRef] [PubMed]
    [Google Scholar]
  33. Spiegel M. , Pichlmair A. , Martínez-Sobrido L. , Cros J. , García-Sastre A. , Haller O. , Weber F. . ( 2005; ). Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. . J Virol 79:, 2079–2086. [CrossRef] [PubMed]
    [Google Scholar]
  34. Sulea T. , Lindner H. A. , Purisima E. O. , Ménard R. . ( 2005; ). Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease?. J Virol 79:, 4550–4551. [CrossRef] [PubMed]
    [Google Scholar]
  35. Tagliaferri P. , Caraglia M. , Budillon A. , Marra M. , Vitale G. , Viscomi C. , Masciari S. , Tassone P. , Abbruzzese A. , Venuta S. . ( 2005; ). New pharmacokinetic and pharmacodynamic tools for interferon-alpha (IFN-alpha) treatment of human cancer. . Cancer Immunol Immunother 54:, 1–10. [CrossRef] [PubMed]
    [Google Scholar]
  36. Tang X. , Gao J. S. , Guan Y. J. , McLane K. E. , Yuan Z. L. , Ramratnam B. , Chin Y. E. . ( 2007; ). Acetylation-dependent signal transduction for type I interferon receptor. . Cell 131:, 93–105. [CrossRef] [PubMed]
    [Google Scholar]
  37. Thiel V. , Ivanov K. A. , Putics A. , Hertzig T. , Schelle B. , Bayer S. , Weissbrich B. , Snijder E. J. , Rabenau H. et al. ( 2003; ). Mechanisms and enzymes involved in SARS coronavirus genome expression. . J Gen Virol 84:, 2305–2315. [CrossRef] [PubMed]
    [Google Scholar]
  38. Tsang K. W. , Ho P. L. , Ooi G. C. , Yee W. K. , Wang T. , Chan-Yeung M. , Lam W. K. , Seto W. H. , Yam L. Y. et al. ( 2003; ). A cluster of cases of severe acute respiratory syndrome in Hong Kong. . N Engl J Med 348:, 1977–1985. [CrossRef] [PubMed]
    [Google Scholar]
  39. Uddin S. , Sassano A. , Deb D. K. , Verma A. , Majchrzak B. , Rahman A. , Malik A. B. , Fish E. N. , Platanias L. C. . ( 2002; ). Protein kinase C-δ (PKC-δ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. . J Biol Chem 277:, 14408–14416. [CrossRef] [PubMed]
    [Google Scholar]
  40. Vantaggiato C. , Formentini I. , Bondanza A. , Bonini C. , Naldini L. , Brambilla R. . ( 2006; ). ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. . J Biol 5:, 14.[PubMed] [CrossRef]
    [Google Scholar]
  41. Varfolomeev E. , Blankenship J. W. , Wayson S. M. , Fedorova A. V. , Kayagaki N. , Garg P. , Zobel K. , Dynek J. N. , Elliott L. O. , Wallweber H. J. A. . ( 2007; ). IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. . Cell 131:, 669–681. [CrossRef] [PubMed]
    [Google Scholar]
  42. Wang J. Y. , Lee C. H. , Cheng S. L. , Chang H. T. , Hsu Y. L. , Wang H. C. , Chu S. H. . ( 2004; a). Comparison of the clinical manifestations of severe acute respiratory syndrome and Mycoplasma pneumoniae pneumonia. . J Formos Med Assoc 103:, 894–899.[PubMed]
    [Google Scholar]
  43. Wang W. K. , Chen S. Y. , Liu I. J. , Kao C. L. , Chen H. L. , Chiang B. L. , Wang J. T. , Sheng W. H. , Hsueh P. R. et al. ( 2004; b). Temporal relationship of viral load, ribavirin, interleukin (IL)-6, IL-8, and clinical progression in patients with severe acute respiratory syndrome. . Clin Infect Dis 39:, 1071–1075. [CrossRef] [PubMed]
    [Google Scholar]
  44. Wong C. K. , Lam C. W. , Wu A. K. , Ip W. K. , Lee N. L. , Chan I. H. , Lit L. C. , Hui D. S. , Chan M. H. et al. ( 2004; ). Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. . Clin Exp Immunol 136:, 95–103. [CrossRef] [PubMed]
    [Google Scholar]
  45. Yan H. , Xiao G. , Zhang J. , Hu Y. , Yuan F. , Cole D. K. , Zheng C. , Gao G. F. . ( 2004; ). SARS coronavirus induces apoptosis in Vero E6 cells. . J Med Virol 73:, 323–331. [CrossRef] [PubMed]
    [Google Scholar]
  46. Zampieri C. A. , Fortin J. F. , Nolan G. P. , Nabel G. J. . ( 2007; ). The ERK mitogen-activated protein kinase pathway contributes to Ebola virus glycoprotein-induced cytotoxicity. . J Virol 81:, 1230–1240. [CrossRef] [PubMed]
    [Google Scholar]
  47. Zhao C. , Denison C. , Huibregtse J. M. , Gygi S. , Krug R. M. . ( 2005; ). Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. . Proc Natl Acad Sci U S A 102:, 10200–10205. [CrossRef] [PubMed]
    [Google Scholar]
  48. Ziebuhr J. . ( 2004; ). Molecular biology of severe acute respiratory syndrome coronavirus. . Curr Opin Microbiol 7:, 412–419. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.028936-0
Loading
/content/journal/jgv/10.1099/vir.0.028936-0
Loading

Data & Media loading...

Supplements

vol. , part 5, pp. 1127 - 1140

Effect of PD098059 treatment on IFN-α-induced expression of 2'-5'-OAS in vector control cells and PLpro-expressing cells

Effect of U0126 treatment on IFN-α-induced phosphorylation of STAT1 in vector control cells and PLpro-expressing cells

Western blotting analysis of ERK1 in mock cells and HCoV-NL63-infected cells

Effect of PLpro expression in A549 cells on IFN-α-induced phosphorylation of ERK1/2 and STAT1 [Single PDF file](201 KB)



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