NCOA2 promotes lytic reactivation of Kaposi’s sarcoma-associated herpesvirus by enhancing the expression of the master switch protein RTA

English version

Autoři: Xiaoqin Wei ^aff001; Lei Bai ^aff001; Lianghui Dong ^aff001; Huimei Liu ^aff001; Peidong Xing ^aff001; Zhiyao Zhou ^aff002; Shuwen Wu ^aff001; Ke Lan ^aff001
Působiště autorů: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China ^aff001; University College London, Gower Street, London, United Kingdom ^aff002
Vyšlo v časopise: NCOA2 promotes lytic reactivation of Kaposi’s sarcoma-associated herpesvirus by enhancing the expression of the master switch protein RTA. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008160
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008160

Souhrn

Reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV) is important for persistent infection in the host as well as viral oncogenesis. The replication and transcription activator (RTA) encoded by KSHV ORF50 plays a central role in the switch from viral latency to lytic replication. Given that RTA is a transcriptional activator and RTA expression is sufficient to activate complete lytic replication, RTA must possess an elaborate mechanism for regulating its protein abundance. Previous studies have demonstrated that RTA could be degraded through the ubiquitin-proteasome pathway. A protein abundance regulatory signal (PARS), which consists of PARS I and PARS II, at the C-terminal region of RTA modulates its protein abundance. In the present study, we identified a host protein named Nuclear receptor coactivator 2 (NCOA2), which can interact with RTA in vitro and in vivo. We further showed that NCOA2 binds to the PARS II domain of RTA. We demonstrated that NCOA2 enhances RTA stability and prevents the proteasome-mediated degradation of RTA by competing with MDM2, an E3 ubiquitin ligase of RTA that interacts with the PARS II domain. Moreover, overexpression of NCOA2 in KSHV-infected cells significantly enhanced the expression level of RTA, which promotes the expression of RTA downstream viral lytic genes and lytic replication. In contrast, silencing of endogenous NCOA2 downregulated the expression of viral lytic genes and impaired viral lytic replication. Interestingly, we also found that RTA upregulates the expression of NCOA2 during lytic reactivation. Taken together, our data support the conclusion that NCOA2 is a novel RTA-binding protein that promotes RTA-driven lytic reactivation by increasing the stability of RTA, and the RTA-NCOA2 positive feedback regulatory loop plays an important role in KSHV reactivation.

Klíčová slova:

293T cells – DNA transcription – Immunoprecipitation – Kaposi's sarcoma-associated herpesvirus – Plasmid construction – Ubiquitination – Viral gene expression – Viral replication

Zdroje

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266(5192):1865–9. doi: 10.1126/science.7997879 7997879

2. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995;86(4):1276–80. 7632932

3. Bhutani M, Polizzotto MN, Uldrick TS, Yarchoan R. Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Seminars in oncology. 2015;42(2):223–46. doi: 10.1053/j.seminoncol.2014.12.027 25843728

4. Ye F, Lei X, Gao SJ. Mechanisms of Kaposi's Sarcoma-Associated Herpesvirus Latency and Reactivation. Advances in virology. 2011;2011.

5. Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J Virol. 1998;72(2):1005–12. 9444993

6. Speck SH, Ganem D. Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe. 2010;8(1):100–15. doi: 10.1016/j.chom.2010.06.014 20638646

7. Gramolelli S, Schulz TF. The role of Kaposi sarcoma-associated herpesvirus in the pathogenesis of Kaposi sarcoma. The Journal of pathology. 2015;235(2):368–80. doi: 10.1002/path.4441 25212381

8. Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, Tosato G, et al. Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood. 2001;97(10):3244–50. doi: 10.1182/blood.v97.10.3244 11342455

9. Ye F, Zhou F, Bedolla RG, Jones T, Lei X, Kang T, et al. Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog. 2011;7(5):e1002054. doi: 10.1371/journal.ppat.1002054 21625536

10. Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc Natl Acad Sci U S A. 2009;106(28):11725–30. doi: 10.1073/pnas.0905316106 19564611

11. Bubman D, Cesarman E. Pathogenesis of Kaposi's sarcoma. Hematology/oncology clinics of North America. 2003;17(3):717–45. doi: 10.1016/s0889-8588(03)00044-3 12852653

12. Li DJ, Verma D, Mosbruger T, Swaminathan S. CTCF and Rad21 act as host cell restriction factors for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription. PLoS Pathog. 2014;10(1):e1003880. doi: 10.1371/journal.ppat.1003880 24415941

13. Grundhoff A, Ganem D. Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest. 2004;113(1):124–36. doi: 10.1172/JCI200417803 14702116

14. Dourmishev LA, Dourmishev AL, Palmeri D, Schwartz RA, Lukac DM. Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiology and molecular biology reviews: MMBR. 2003;67(2):175–212, table of contents. doi: 10.1128/MMBR.67.2.175-212.2003 12794189

15. Glesby MJ, Hoover DR, Weng S, Graham NM, Phair JP, Detels R, et al. Use of antiherpes drugs and the risk of Kaposi's sarcoma: data from the Multicenter AIDS Cohort Study. The Journal of infectious diseases. 1996;173(6):1477–80. doi: 10.1093/infdis/173.6.1477 8648224

16. Coen N, Duraffour S, Snoeck R, Andrei G. KSHV targeted therapy: an update on inhibitors of viral lytic replication. Viruses. 2014;6(11):4731–59. doi: 10.3390/v6114731 25421895

17. Zhu X, Guo Y, Yao S, Yan Q, Xue M, Hao T, et al. Synergy between Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 and HIV-1 Nef protein in promotion of angiogenesis and oncogenesis: role of the AKT signaling pathway. Oncogene. 2014;33(15):1986–96. doi: 10.1038/onc.2013.136 23604117

18. Lukac DM, Kirshner JR, Ganem D. Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol. 1999;73(11):9348–61. 10516043

19. Lukac DM, Garibyan L, Kirshner JR, Palmeri D, Ganem D. DNA binding by Kaposi's sarcoma-associated herpesvirus lytic switch protein is necessary for transcriptional activation of two viral delayed early promoters. J Virol. 2001;75(15):6786–99. doi: 10.1128/JVI.75.15.6786-6799.2001 11435557

20. Gradoville L, Gerlach J, Grogan E, Shedd D, Nikiforow S, Metroka C, et al. Kaposi's sarcoma-associated herpesvirus open reading frame 50/Rta protein activates the entire viral lytic cycle in the HH-B2 primary effusion lymphoma cell line. J Virol. 2000;74(13):6207–12. doi: 10.1128/jvi.74.13.6207-6212.2000 10846108

21. Deng H, Young A, Sun R. Auto-activation of the rta gene of human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus. J Gen Virol. 2000;81(Pt 12):3043–8. doi: 10.1099/0022-1317-81-12-3043 11086135

22. Liang Y, Chang J, Lynch SJ, Lukac DM, Ganem D. The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jkappa (CSL), the target of the Notch signaling pathway. Genes & development. 2002;16(15):1977–89.

23. Wang Y, Li H, Chan MY, Zhu FX, Lukac DM, Yuan Y. 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(16):8615–29. doi: 10.1128/JVI.78.16.8615-8629.2004 15280471

24. Chang PJ, Miller G. Autoregulation of DNA binding and protein stability of Kaposi's sarcoma-associated herpesvirus ORF50 protein. J Virol. 2004;78(19):10657–73. doi: 10.1128/JVI.78.19.10657-10673.2004 15367633

25. Guito J, Lukac DM. KSHV reactivation and novel implications of protein isomerization on lytic switch control. Viruses. 2015;7(1):72–109. doi: 10.3390/v7010072 25588053

26. Gwack Y, Byun H, Hwang S, Lim C, Choe J. CREB-binding protein and histone deacetylase regulate the transcriptional activity of Kaposi's sarcoma-associated herpesvirus open reading frame 50. J Virol. 2001;75(4):1909–17. doi: 10.1128/JVI.75.4.1909-1917.2001 11160690

27. Zhang L, Chiu J, Lin JC. Activation of human herpesvirus 8 (HHV-8) thymidine kinase (TK) TATAA-less promoter by HHV-8 ORF50 gene product is SP1 dependent. DNA and cell biology. 1998;17(9):735–42. doi: 10.1089/dna.1998.17.735 9778032

28. Wang SE, Wu FY, Chen H, Shamay M, Zheng Q, Hayward GS. Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway. J Virol. 2004;78(8):4248–67. doi: 10.1128/JVI.78.8.4248-4267.2004 15047839

29. Sakakibara S, Ueda K, Chen J, Okuno T, Yamanishi K. Octamer-binding sequence is a key element for the autoregulation of Kaposi's sarcoma-associated herpesvirus ORF50/Lyta gene expression. J Virol. 2001;75(15):6894–900. doi: 10.1128/JVI.75.15.6894-6900.2001 11435569

30. Yang Z, Wood C. The transcriptional repressor K-RBP modulates RTA-mediated transactivation and lytic replication of Kaposi's sarcoma-associated herpesvirus. J Virol. 2007;81(12):6294–306. doi: 10.1128/JVI.02648-06 17409159

31. Yang Z, Yan Z, Wood C. Kaposi's sarcoma-associated herpesvirus transactivator RTA promotes degradation of the repressors to regulate viral lytic replication. J Virol. 2008;82(7):3590–603. doi: 10.1128/JVI.02229-07 18216089

32. Yang Z, Wen HJ, Minhas V, Wood C. The zinc finger DNA-binding domain of K-RBP plays an important role in regulating Kaposi's sarcoma-associated herpesvirus RTA-mediated gene expression. Virology. 2009;391(2):221–31. doi: 10.1016/j.virol.2009.06.014 19592062

33. Yu Y, Wang SE, Hayward GS. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity. 2005;22(1):59–70. doi: 10.1016/j.immuni.2004.11.011 15664159

34. Moll UM, Petrenko O. The MDM2-p53 interaction. Molecular cancer research: MCR. 2003;1(14):1001–8. 14707283

35. Chang TH, Wang SS, Chen LW, Shih YJ, Chang LK, Liu ST, et al. Regulation of the Abundance of Kaposi's Sarcoma-Associated Herpesvirus ORF50 Protein by Oncoprotein MDM2. PLoS Pathog. 2016;12(10):e1005918. doi: 10.1371/journal.ppat.1005918 27698494

36. Chang PJ, Shedd D, Miller G. A mobile functional region of Kaposi's sarcoma-associated herpesvirus ORF50 protein independently regulates DNA binding and protein abundance. J Virol. 2008;82(19):9700–16. doi: 10.1128/JVI.00862-08 18653447

37. Jaber T, Yuan Y. A virally encoded small peptide regulates RTA stability and facilitates Kaposi's sarcoma-associated herpesvirus lytic replication. J Virol. 2013;87(6):3461–70. doi: 10.1128/JVI.02746-12 23302891

38. Purushothaman P, Uppal T, Verma SC. Molecular biology of KSHV lytic reactivation. Viruses. 2015;7(1):116–53. doi: 10.3390/v7010116 25594835

39. Shaw RN, Arbiser JL, Offermann MK. Valproic acid induces human herpesvirus 8 lytic gene expression in BCBL-1 cells. Aids. 2000;14(7):899–902. doi: 10.1097/00002030-200005050-00021 10839602

40. Coppo M, Chinenov Y, Sacta MA, Rogatsky I. The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis. Nature communications. 2016;7:12254. doi: 10.1038/ncomms12254 27464507

41. Brulois K, Toth Z, Wong LY, Feng P, Gao SJ, Ensser A, et al. Kaposi's sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol. 2014;88(16):9335–49. doi: 10.1128/JVI.00873-14 24899205

42. Myoung J, Ganem D. Generation of a doxycycline-inducible KSHV producer cell line of endothelial origin: maintenance of tight latency with efficient reactivation upon induction. Journal of virological methods. 2011;174(1–2):12–21. doi: 10.1016/j.jviromet.2011.03.012 21419799

43. Edelman DC. Human herpesvirus 8—a novel human pathogen. Virology journal. 2005;2:78. doi: 10.1186/1743-422X-2-78 16138925

44. Lukac DM, Yuan Y. Reactivation and lytic replication of KSHV. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge2007.

45. Greene W, Kuhne K, Ye F, Chen J, Zhou F, Lei X, et al. Molecular biology of KSHV in relation to AIDS-associated oncogenesis. Cancer treatment and research. 2007;133:69–127. doi: 10.1007/978-0-387-46816-7_3 17672038

46. Aneja KK, Yuan Y. Reactivation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus: An Update. Front Microbiol. 2017;8:613. doi: 10.3389/fmicb.2017.00613 28473805

47. Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. The New England journal of medicine. 1999;340(14):1063–70. doi: 10.1056/NEJM199904083401402 10194235

48. Bechtel JT, Liang Y, Hvidding J, Ganem D. Host range of Kaposi's sarcoma-associated herpesvirus in cultured cells. J Virol. 2003;77(11):6474–81. doi: 10.1128/JVI.77.11.6474-6481.2003 12743304

49. Carroll KD, Khadim F, Spadavecchia S, Palmeri D, Lukac DM. Direct interactions of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 ORF50/Rta protein with the cellular protein octamer-1 and DNA are critical for specifying transactivation of a delayed-early promoter and stimulating viral reactivation. J Virol. 2007;81(16):8451–67. doi: 10.1128/JVI.00265-07 17537858

50. Gwack Y, Nakamura H, Lee SH, Souvlis J, Yustein JT, Gygi S, et al. Poly(ADP-ribose) polymerase 1 and Ste20-like kinase hKFC act as transcriptional repressors for gamma-2 herpesvirus lytic replication. Molecular and cellular biology. 2003;23(22):8282–94. doi: 10.1128/MCB.23.22.8282-8294.2003 14585985

51. He Z, Liu Y, Liang D, Wang Z, Robertson ES, Lan K. Cellular corepressor TLE2 inhibits replication-and-transcription- activator-mediated transactivation and lytic reactivation of Kaposi's sarcoma-associated herpesvirus. J Virol. 2010;84(4):2047–62. doi: 10.1128/JVI.01984-09 19939918

52. Leo C, Chen JD. The SRC family of nuclear receptor coactivators. Gene. 2000;245(1):1–11. doi: 10.1016/s0378-1119(00)00024-x 10713439

53. Duteil D, Chambon C, Ali F, Malivindi R, Zoll J, Kato S, et al. The transcriptional coregulators TIF2 and SRC-1 regulate energy homeostasis by modulating mitochondrial respiration in skeletal muscles. Cell metabolism. 2010;12(5):496–508. doi: 10.1016/j.cmet.2010.09.016 21035760

54. Xu J, Wu RC, O'Malley BW. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nature reviews Cancer. 2009;9(9):615–30. doi: 10.1038/nrc2695 19701241

55. Li Y, Low HQ, Foo JN, Darabi H, Einarsdomicronttir K, Humphreys K, et al. Genetic variants in ER cofactor genes and endometrial cancer risk. PLoS One. 2012;7(8):e42445. doi: 10.1371/journal.pone.0042445 22876322

56. An CH, Park SW, Yoo NJ, Lee SH. Mutational analysis of NCOA2 gene in prostate cancer and other common cancers. APMIS: acta pathologica, microbiologica, et immunologica Scandinavica. 2011;119(4–5):317–8. doi: 10.1111/j.1600-0463.2011.02734.x 21492233

57. Cai M, Liang X, Sun X, Chen H, Dong Y, Wu L, et al. Nuclear Receptor Coactivator 2 Promotes Human Breast Cancer Cell Growth by Positively Regulating the MAPK/ERK Pathway. Frontiers in oncology. 2019;9:164. doi: 10.3389/fonc.2019.00164 30941313

58. York B, O'Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem. 2010;285(50):38743–50. doi: 10.1074/jbc.R110.193367 20956538

59. Zhao Q, Liang D, Sun R, Jia B, Xia T, Xiao H, et al. Kaposi's sarcoma-associated herpesvirus-encoded replication and transcription activator impairs innate immunity via ubiquitin-mediated degradation of myeloid differentiation factor 88. J Virol. 2015;89(1):415–27. doi: 10.1128/JVI.02591-14 25320320

60. Lin X, Sun R, Zhang F, Gao Y, Bin L, Lan K. The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency. J Virol. 2017;91(17).

61. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nature methods. 2014;11(8):783–4. doi: 10.1038/nmeth.3047 25075903