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NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target

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Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), often fatal malignancies afflicting HIV-infected patients. Previous research has shown that blockade of the ubiquitin proteasome system (UPS, a normal quality control pathway that degrades cellular proteins) is able to kill KSHV-infected lymphoma cells. A large component of the UPS is made up by the protein family known as the cullin-RING ubiquitin ligases (CRLs), which are activated by NEDD8 (a process known as NEDDylation). Recently, an inhibitor of NEDDylation (MLN4924) was developed and is currently in clinical trials as an anti-cancer drug. As NEDDylation has not been investigated for many viruses, we used this to compound examine its importance in KSHV biology. Firstly we show that NEDDylation is essential for the viability of KSHV-infected lymphoma cells, and MLN4924 treatment killed these cells by blocking NF-κB activity (required for KSHV latency gene expression and KSHV-associated cancer). Furthermore, we show that NEDDylation is required for KSHV to replicate its genome, a critical step in the production of new virus particles. Therefore, this research has identified a novel molecular mechanism that governs KSHV replication. Furthermore, it demonstrates that NEDDylation is a viable target for the treatment of KSHV-associated malignancies.

Vyšlo v časopise: NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004771
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004771

Souhrn

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), often fatal malignancies afflicting HIV-infected patients. Previous research has shown that blockade of the ubiquitin proteasome system (UPS, a normal quality control pathway that degrades cellular proteins) is able to kill KSHV-infected lymphoma cells. A large component of the UPS is made up by the protein family known as the cullin-RING ubiquitin ligases (CRLs), which are activated by NEDD8 (a process known as NEDDylation). Recently, an inhibitor of NEDDylation (MLN4924) was developed and is currently in clinical trials as an anti-cancer drug. As NEDDylation has not been investigated for many viruses, we used this to compound examine its importance in KSHV biology. Firstly we show that NEDDylation is essential for the viability of KSHV-infected lymphoma cells, and MLN4924 treatment killed these cells by blocking NF-κB activity (required for KSHV latency gene expression and KSHV-associated cancer). Furthermore, we show that NEDDylation is required for KSHV to replicate its genome, a critical step in the production of new virus particles. Therefore, this research has identified a novel molecular mechanism that governs KSHV replication. Furthermore, it demonstrates that NEDDylation is a viable target for the treatment of KSHV-associated malignancies.

Zdroje

1. Kisselev AF, van der Linden WA, Overkleeft HS. Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol. 2012;19 : 99–115. doi: 10.1016/j.chembiol.2012.01.003 22284358

2. Boulanger E, Meignin V, Oksenhendler E. Bortezomib (PS-341) in patients with human herpesvirus 8-associated primary effusion lymphoma. Br J Haematol. 2008;141 : 559–561. doi: 10.1111/j.1365-2141.2008.07057.x 18341641

3. Brown HJ, McBride WH, Zack JA, Sun R. Prostratin and bortezomib are novel inducers of latent Kaposi's sarcoma-associated herpesvirus. Antivir Ther. 2005;10 : 745–751. 16218174

4. Matta H, Chaudhary PM. The proteasome inhibitor bortezomib (PS-341) inhibits growth and induces apoptosis in primary effusion lymphoma cells. Cancer Biol Ther. 2005;4 : 77–82. 15662128

5. Sarosiek KA, Cavallin LE, Bhatt S, Toomey NL, Natkunam Y, et al. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A. 2010;107 : 13069–13074. doi: 10.1073/pnas.1002985107 20615981

6. Dittmer DP, Damania B. Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update. Curr Opin Virol. 2013;3 : 238–244. doi: 10.1016/j.coviro.2013.05.012 23769237

7. Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010; 10 : 707–719. doi: 10.1038/nrc2888 20865011

8. La Ferla L, Pinzone MR, Nunnari G, Martellotta F, Lleshi A, et al. Kaposi' s sarcoma in HIV-positive patients: the state of art in the HAART-era. Eur Rev Med Pharmacol Sci. 2013;17 : 2354–2365. 24065230

9. Simonelli C, Spina M, Cinelli R, Talamini R, Tedeschi R, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol. 2003;21 : 3948–3954. 14581418

10. Gantt S, Casper C. Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. Curr Opin Infect Dis. 2011;24 : 295–301. doi: 10.1097/QCO.0b013e3283486d04 21666458

11. Bhatt S, Ashlock BM, Toomey NL, Diaz LA, Mesri EA, et al. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest. 2013;123 : 2616–2628. doi: 10.1172/JCI64503 23635777

12. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458 : 732–736. doi: 10.1038/nature07884 19360080

13. Sarikas A, Hartmann T, Pan ZQ. The cullin protein family. Genome Biol. 2011;12 : 220. doi: 10.1186/gb-2011-12-4-220 21554755

14. Bennett EJ, Rush J, Gygi SP, Harper JW. Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell. 2010;143 : 951–965. doi: 10.1016/j.cell.2010.11.017 21145461

15. Rabut G, Peter M. Function and regulation of protein neddylation. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep. 2008;9 : 969–976. doi: 10.1038/embor.2008.183 18802447

16. Wimmer P, Schreiner S, Dobner T. Human pathogens and the host cell SUMOylation system. J Virol. 2012;86 : 642–654. doi: 10.1128/JVI.06227-11 22072786

17. Everett RD, Boutell C, Hale BG. Interplay between viruses and host sumoylation pathways. Nat Rev Microbiol. 2013;11 : 400–411. doi: 10.1038/nrmicro3015 23624814

18. Gastaldello S, Hildebrand S, Faridani O, Callegari S, Palmkvist M, et al. A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases. Nat Cell Biol. 2010;12 : 351–361. doi: 10.1038/ncb2035 20190741

19. Stanley DJ, Bartholomeeusen K, Crosby DC, Kim DY, Kwon E, et al. Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G. PLoS Pathog. 2012;8: e1003085. doi: 10.1371/journal.ppat.1003085 23300442

20. Romani B, Engelbrecht S, Glashoff RH. Antiviral roles of APOBEC proteins against HIV-1 and suppression by Vif. Arch Virol. 2009;154 : 1579–1588. doi: 10.1007/s00705-009-0481-y 19669862

21. Yu X, Yu Y, Liu B, Luo K, Kong W, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science. 2003;302 : 1056–1060. 14564014

22. Cai QL, Knight JS, Verma SC, Zald P, Robertson ES. EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog. 2006;2: e116. 17069461

23. Hannah J, Zhou P. Regulation of DNA damage response pathways by the cullin-RING ubiquitin ligases. DNA Repair (Amst). 2009;8 : 536–543. doi: 10.1016/j.dnarep.2009.01.011 19231300

24. O'Dowd JM, Zavala AG, Brown CJ, Mori T, Fortunato EA. HCMV-infected cells maintain efficient nucleotide excision repair of the viral genome while abrogating repair of the host genome. PLoS Pathog. 2012;8: e1003038. doi: 10.1371/journal.ppat.1003038 23209410

25. Soucy TA, Dick LR, Smith PG, Milhollen MA, Brownell JE. The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy. Genes Cancer. 2010;1 : 708–716. doi: 10.1177/1947601910382898 21779466

26. Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, et al. Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer Res. 2011;71 : 3042–3051. doi: 10.1158/0008-5472.CAN-10-2122 21487042

27. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood. 2010;116 : 1515–1523. doi: 10.1182/blood-2010-03-272567 20525923

28. de Oliveira DE, Ballon G, Cesarman E. NF-kappaB signaling modulation by EBV and KSHV. Trends Microbiol. 2010;18 : 248–257. doi: 10.1016/j.tim.2010.04.001 20452220

29. Majerciak V, Kruhlak M, Dagur PK, McCoy JP, Zheng ZM Jr.. Caspase-7 cleavage of Kaposi sarcoma-associated herpesvirus ORF57 confers a cellular function against viral lytic gene expression. J Biol Chem. 2010;285 : 11297–11307. doi: 10.1074/jbc.M109.068221 20159985

30. Sun R, Lin SF, Staskus K, Gradoville L, Grogan E, et al. Kinetics of Kaposi's sarcoma-associated herpesvirus gene expression. J Virol. 1999;73 : 2232–2242. 9971806

31. Pearce M, Matsumura S, Wilson AC. Transcripts Encoding K12, v-FLIP, v-Cyclin, and the MicroRNA Cluster of Kaposi's Sarcoma-Associated Herpesvirus Originate from a Common Promoter. J Virol. 2005;79 : 14457–14464. 16254382

32. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18 : 621–663. 10837071

33. Jha HC, Upadhyay SK, M AJP, Lu J, Cai Q, et al. H2AX phosphorylation is important for LANA-mediated Kaposi's sarcoma-associated herpesvirus episome persistence. J Virol. 2013;87 : 5255–5269. doi: 10.1128/JVI.03575-12 23449797

34. Lei X, Bai Z, Ye F, Xie J, Kim CG, et al. Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol. 2010;12 : 193–199. doi: 10.1038/ncb2019 20081837

35. Jin J, Ang XL, Shirogane T, Wade Harper J. Identification of substrates for F-box proteins. Methods Enzymol. 2005;399 : 287–309. 16338364

36. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, et al. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell. 2009;36 : 131–140. doi: 10.1016/j.molcel.2009.07.025 19818716

37. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, et al. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature. 1998;396 : 590–594. 9859996

38. Nakagawa T, Xiong Y. X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression. Mol Cell. 2011;43 : 381–391. doi: 10.1016/j.molcel.2011.05.033 21816345

39. Ma T, Chen Y, Zhang F, Yang CY, Wang S, et al. RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Mol Cell. 2013;49 : 897–907. doi: 10.1016/j.molcel.2013.01.006 23394999

40. Rossetto CC, Susilarini NK, Pari GS. nteraction of Kaposi's sarcoma-associated herpesvirus ORF59 with oriLyt is dependent on binding with K-Rta. J Virol. 2011;85 : 3833–3841. doi: 10.1128/JVI.02361-10 21289111

41. Wang Y, Li H, Chan MY, Zhu FX, Lukac DM, et al. Kaposi's sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: cis-acting requirements for replication and ori-Lyt-associated RNA transcription. J Virol. 2004;78 : 8615–8629. 15280471

42. Wang Y, Li H, Tang Q, Maul GG, Yuan Y. Kaposi's sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: involvement of host cellular factors. J Virol. 2008;82 : 2867–2882. doi: 10.1128/JVI.01319-07 18199640

43. Chen W, Hilton IB, Staudt MR, Burd CE, Dittmer DP. Distinct p53, p53:LANA, and LANA complexes in Kaposi's Sarcoma—associated Herpesvirus Lymphomas. J Virol. 2010;84 : 3898–3908. doi: 10.1128/JVI.01321-09 20130056

44. Alkharsah KR, Singh VV, Bosco R, Santag S, Grundhoff A, et al. Deletion of Kaposi's sarcoma-associated herpesvirus FLICE inhibitory protein, vFLIP, from the viral genome compromises the activation of STAT1-responsive cellular genes and spindle cell formation in endothelial cells. J Virol. 2011;85 : 10375–10388. doi: 10.1128/JVI.00226-11 21795355

45. Grossmann C, Podgrabinska S, Skobe M, Ganem D. Activation of NF-kappaB by the latent vFLIP gene of Kaposi's sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype. J Virol. 2006;80 : 7179–7185. 16809323

46. Izumiya Y, Izumiya C, Hsia D, Ellison TJ, Luciw PA, et al. NF-kappaB serves as a cellular sensor of Kaposi's sarcoma-associated herpesvirus latency and negatively regulates K-Rta by antagonizing the RBP-Jkappa coactivator. J Virol. 2009;83 : 4435–4446. doi: 10.1128/JVI.01999-08 19244329

47. Jackson BR, Noerenberg M, Whitehouse A. A novel mechanism inducing genome instability in Kaposi's sarcoma-associated herpesvirus infected cells. PLoS Pathog. 2014;10: e1004098. doi: 10.1371/journal.ppat.1004098 24788796

48. Karttunen H, Savas JN, McKinney C, Chen YH, Yates JR 3rd, et al. Co-opting the Fanconi Anemia Genomic Stability Pathway Enables Herpesvirus DNA Synthesis and Productive Growth. Mol Cell. 2014;55 : 111–22. doi: 10.1016/j.molcel.2014.05.020 24954902

49. Turnell AS, Grand RJ. DNA viruses and the cellular DNA-damage response. J Gen Virol. 2012;93 : 2076–2097. doi: 10.1099/vir.0.044412-0 22855786

50. Jackson SP, Durocher D. Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell. 2013;49 : 795–807. doi: 10.1016/j.molcel.2013.01.017 23416108

51. Bu W, Carroll KD, Palmeri D, Lukac DM. Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 ORF50/Rta lytic switch protein functions as a tetramer. J Virol. 2007;81 : 5788–5806. 17392367

52. Nakamura H, Lu M, Gwack Y, Souvlis J, Zeichner SL, et al. Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator. J Virol. 2003;77 : 4205–4220. 12634378

53. Vieira J O'Hearn PM. Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression. Virology. 2004;325 : 225–240. 15246263

54. Jubelin G, Taieb F, Duda DM, Hsu Y, Samba-Louaka A, et al. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS Pathog. 2010;6: e1001128. doi: 10.1371/journal.ppat.1001128 20941356

55. Hall KT, Giles MS, Calderwood MA, Goodwin DJ, Matthews DA, et al. The Herpesvirus Saimiri open reading frame 73 gene product interacts with the cellular protein p32. J Virol. 2002;76 : 11612–11622. 12388722

56. Jackson BR, Boyne JR, Noerenberg M, Taylor A, Hautbergue GM, et al. An interaction between KSHV ORF57 and UIF provides mRNA-adaptor redundancy in herpesvirus intronless mRNA export. PLoS Pathog. 2011;7: e1002138. doi: 10.1371/journal.ppat.1002138 21814512

57. Boyne JR, Jackson BR, Taylor A, Macnab SA, Whitehouse A. Kaposi's sarcoma-associated herpesvirus ORF57 protein interacts with PYM to enhance translation of viral intronless mRNAs. EMBO J. 2010;29 : 1851–1864. doi: 10.1038/emboj.2010.77 20436455

58. Goodwin DJ, Hall KT, Giles MS, Calderwood MA, Markham AF, et al. The carboxy terminus of the herpesvirus saimiri ORF 57 gene contains domains that are required for transactivation and transrepression. J Gen Virol. 2000;81 : 2253–2265. 10950983

59. Gould F, Harrison SM, Hewitt EW, Whitehouse A. Kaposi's sarcoma-associated herpesvirus RTA promotes degradation of the Hey1 repressor protein through the ubiquitin proteasome pathway. J Virol. 2009;83 : 6727–6738. doi: 10.1128/JVI.00351-09 19369342

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Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation
Článek Transgenic Expression of the Dicotyledonous Pattern Recognition Receptor EFR in Rice Leads to Ligand-Dependent Activation of Defense Responses
Článek Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer
Článek Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
Článok vyšiel v časopise

PLOS Pathogens

2015 Číslo 3
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Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
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