Human cytomegalovirus IE1 protein disrupts interleukin-6 signaling by sequestering STAT3 in the nucleus

Journal of Virology

Volumn 87, Issue 19, 2013, Pages 10763-10776

  Reitsma, Justin M ^a   Sato, Hiromi ^a   Nevels, Michael ^b   Terhune, Scott S ^a   Paulus, Christina ^b  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

^b UNIVERSITY OF REGENSBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

HUMAN CYTOMEGALOVIRUS IE1 PROTEIN; INTERLEUKIN 6; STAT3 PROTEIN; UNCLASSIFIED DRUG; VIRUS PROTEIN;

ARTICLE; BINDING AFFINITY; CELL NUCLEUS; CELLULAR DISTRIBUTION; CONTROLLED STUDY; CYTOMEGALOVIRUS INFECTION; CYTOPLASM; GENE EXPRESSION; GENE TARGETING; HUMAN; HUMAN CELL; HUMAN CYTOMEGALOVIRUS; IL 6 GENE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DNA BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; SOCS3 GENE; VIRUS GENE; VIRUS GENOME; VIRUS REPLICATION;

HUMAN HERPESVIRUS 5;

EID: 84886016486     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.01197-13     Document Type: Article

References (76)

1. Mocarski E, Shenk T, Pass RF. 2007. Cytomegaloviruses, p 2701-2772. In Knipe DM, Howley PM, Griffin PE, Lamb RA, Martin MA, Roizman B, Straus SE (ed), Fields virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
2. Nassetta L, Kimberlin D, Whitley R. 2009. Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies. J. Antimicrob. Chemother. 63:862-867.
3. Avery RK. 2008. Update in management of ganciclovir-resistant cytomegalovirus infection. Curr. Opin. Infect. Dis. 21:433-437.
4. Hakki M, Chou S. 2011. The biology of cytomegalovirus drug resistance. Curr. Opin. Infect. Dis. 24:605-611.
5. Lurain NS, Chou S. 2010. Antiviral drug resistance of human cytomegalovirus. Clin. Microbiol. Rev. 23:689-712.
6. Greaves RF, Brown JM, Vieira J, Mocarski ES. 1995. Selectable insertion and deletion mutagenesis of the human cytomegalovirus genome using the Escherichia coli guanosine phosphoribosyl transferase (gpt) gene. J. Gen. Virol. 76:2151-2160.
7. Greaves RF, Mocarski ES. 1998. Defective growth correlates with reduced accumulation of a viral DNA replication protein after low-multiplicity infection by a human cytomegalovirus ie1 mutant. J. Virol. 72:366-379.
8. Mocarski ES, Kemble GW, Lyle JM, Greaves RF. 1996. A deletion mutant in the human cytomegalovirus gene encoding IE1(491aa) is replication defective due to a failure in autoregulation. Proc. Natl. Acad. Sci. U.S.A. 93:11321-11326.
9. Ahn JH, Hayward GS. 1997. The major immediate-early proteins IE1 and IE2 of human cytomegalovirus colocalize with and disrupt PMLassociated nuclear bodies at very early times in infected permissive cells. J. Virol. 71:4599-4613.
10. Korioth F, Maul GG, Plachter B, Stamminger T, Frey J. 1996. The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1. Exp. Cell Res. 229:155-158.
11. Wilkinson GW, Kelly C, Sinclair JH, Rickards C. 1998. Disruption of PML-associated nuclear bodies mediated by the human cytomegalovirus major immediate early gene product. J. Gen. Virol. 79:1233-1245.
12. Lafemina RL, Pizzorno MC, Mosca JD, Hayward GS. 1989. Expression of the acidic nuclear immediate-early protein (IE1) of human cytomegalovirus in stable cell lines and its preferential association with metaphase chromosomes. Virology 172:584-600.
13. Huh YH, Kim YE, Kim ET, Park JJ, Song MJ, Zhu H, Hayward GS, Ahn JH. 2008. Binding STAT2 by the acidic domain of human cytomegalovirus IE1 promotes viral growth and is negatively regulated by SUMO. J. Virol. 82:10444-10454.
14. Krauss S, Kaps J, Czech N, Paulus C, Nevels M. 2009. Physical requirements and functional consequences of complex formation between the cytomegalovirus IE1 protein and human STAT2. J. Virol. 83:12854-12870.
15. Paulus C, Krauss S, Nevels M. 2006. A human cytomegalovirus antagonist of type I IFN-dependent signal transducer and activator of transcription signaling. Proc. Natl. Acad. Sci. U.S.A. 103:3840-3845.
16. Jaworska J, Gravel A, Flamand L. 2010. Divergent susceptibilities of human herpesvirus 6 variants to type I interferons. Proc. Natl. Acad. Sci. U.S.A. 107:8369-8374.
17. Knoblach T, Grandel B, Seiler J, Nevels M, Paulus C. 2011. Human cytomegalovirus IE1 protein elicits a type II interferon-like host cell response that depends on activated STAT1 but not interferon-gamma. PLoS Pathog. 7(4):e1002016. doi:10.1371/journal.ppat.1002016.
18. Yu H, Pardoll D, Jove R. 2009. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9:798-809.
19. Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, Murray-Tait V, Chiarle R, Poli V. 2004. The STAT3 isoforms alpha and beta have unique and specific functions. Nat. Immunol. 5:401-409.
20. Yoo JY, Huso DL, Nathans D, Desiderio S. 2002. Specific ablation of Stat3β distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell 108:331-344.
21. Zammarchi F, de Stanchina E, Bournazou E, Supakorndej T, Martires K, Riedel E, Corben AD, Bromberg JF, Cartegni L. 2011. Antitumorigenic potential of STAT3 alternative splicing modulation. Proc. Natl. Acad. Sci. U.S.A. 108:17779-17784.
22. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B. 2009. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship?. Ann. N. Y. Acad. Sci. 1171:59-76.
23. Cimica V, Chen HC, Iyer JK, Reich NC. 2011. Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importinbeta1. PLoS One 6(5):e20188. doi:10.1371/journal.pone.0020188.
24. Liu L, McBride KM, Reich NC. 2005. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-α3. Proc. Natl. Acad. Sci. U.S.A. 102:8150-8155.
25. Wen Z, Darnell JE, Jr. 1997. Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence onDNAbinding of Stat1 and Stat3. Nucleic Acids Res. 25:2062-2067.
26. Wen Z, Zhong Z, Darnell JE, Jr. 1995. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241-250.
27. Reich NC, Liu L. 2006. Tracking STAT nuclear traffic. Nat. Rev. Immunol. 6:602-612.
28. Timofeeva OA, Chasovskikh S, Lonskaya I, Tarasova NI, Khavrutskii L, Tarasov SG, Zhang X, Korostyshevskiy VR, Cheema A, Zhang L, Dakshanamurthy S, Brown ML, Dritschilo A. 2012. Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J. Biol. Chem. 287:14192-14200.
29. Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE, Stark GR. 2005. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 65:939-947.
30. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. 2007. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev. 21:1396-1408.
31. Yu D, Smith GA, Enquist LW, Shenk T. 2002. Construction of a selfexcisable bacterial artificial chromosome containing the human cytomegalovirus genome and mutagenesis of the diploid TRL/IRL13 gene. J. Virol. 76:2316-2328.
32. Reitsma JM, Savaryn JP, Faust K, Sato H, Halligan BD, Terhune SS. 2011. Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest. Cell Host Microbe 9:103-114.
33. Marchini A, Liu H, Zhu H. 2001. Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes. J. Virol. 75:1870-1878.
34. Sinzger C, Hahn G, Digel M, Katona R, Sampaio KL, Messerle M, Hengel H, Koszinowski U, Brune W, Adler B. 2008. Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J. Gen. Virol. 89:359-368.
35. Mitchell DP, Savaryn JP, Moorman NJ, Shenk T, Terhune SS. 2009. Human cytomegalovirus UL28 and UL29 open reading frames encode a spliced mRNA and stimulate accumulation of immediate-early RNAs. J. Virol. 83:10187-10197.
36. Terhune SS, Moorman NJ, Cristea IM, Savaryn JP, Cuevas-Bennett C, Rout MP, Chait BT, Shenk T. 2010. Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA. PLoS Pathog. 6(6):e1000965. doi:101371/journal.ppat.1000965.
37. Yu H, Kortylewski M, Pardoll D. 2007. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7:41-51.
38. Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J. 2007. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl. Acad. Sci. U.S.A. 104:7391-7396.
39. Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar NB. 2012. Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur. J. Cancer Prev. 21:407-412.
40. Bill MA, Fuchs JR, Li C, Yui J, Bakan C, Benson DM, Jr, Schwartz EB, Abdelhamid D, Lin J, Hoyt DG, Fossey SL, Young GS, Carson WE, III, Li PK, Lesinski GB. 2010. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. Mol. Cancer 9:165. doi:10.1186/1476-4598-9-165.
41. Fossey SL, Bear MD, Lin J, Li C, Schwartz EB, Li PK, Fuchs JR, Fenger J, Kisseberth WC, London CA. 2011. The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines. BMC Cancer 11:112. doi:10.1186/1471 -2407-11-112.
42. Kumar A, Bora U. 2012. Molecular docking studies on inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with amino acids. Bioinformation. 8:988-993.
43. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. 2006. Stattic: a smallmolecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13:1235-1242.
44. Ferrajoli A, Faderl S, Van Q, Koch P, Harris D, Liu Z, Hazan-Halevy I, Wang Y, Kantarjian HM, Priebe W, Estrov Z. 2007. WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res. 67:11291-11299.
45. Fehr AR, Gualberto NC, Savaryn JP, Terhune SS, Yu D. 2012. Proteasome-dependent disruption of the E3 ubiquitin ligase anaphasepromoting complex by HCMV protein pUL21a. PLoS Pathog. 8(7): e1002789. doi:10.1371/journal.ppat.1002789.
46. Stenberg RM, Depto AS, Fortney J, Nelson JA. 1989. Regulated expression of early and late RNAs and proteins from the human cytomegalovirus immediate-early gene region. J. Virol. 63:2699-2708.
47. Tenney DJ, Colberg-Poley AM. 1991. Human cytomegalovirus UL36-38 and US3 immediate-early genes: temporally regulated expression of nuclear, cytoplasmic, and polysome-associated transcripts during infection. J. Virol. 65:6724-6734.
48. Heider JA, Bresnahan WA, Shenk TE. 2002. Construction of a rationally designed human cytomegalovirus variant encoding a temperaturesensitive immediate-early 2 protein. Proc. Natl. Acad. Sci. U.S.A. 99: 3141-3146.
49. Loregian A, Appleton BA, Hogle JM, Coen DM. 2004. Residues of human cytomegalovirus DNA polymerase catalytic subunit UL54 that are necessary and sufficient for interaction with the accessory protein UL44. J. Virol. 78:158-167.
50. Loregian A, Appleton BA, Hogle JM, Coen DM. 2004. Specific residues in the connector loop of the human cytomegalovirus DNA polymerase accessory protein UL44 are crucial for interaction with the UL54 catalytic subunit. J. Virol. 78:9084-9092.
51. Sanders RL, Clark CL, Morello CS, Spector DH. 2008. Development of cell lines that provide tightly controlled temporal translation of the human cytomegalovirus IE2 proteins for complementation and functional analyses of growth-impaired and nonviable IE2 mutant viruses. J. Virol. 82: 7059-7077.
52. Stasiak PC, Mocarski ES. 1992. Transactivation of the cytomegalovirus ICP36 gene promoter requires the alpha gene product TRS1 in addition to IE1 and IE2. J. Virol. 66:1050-1058.
53. Weiland KL, Oien NL, Homa F, Wathen MW. 1994. Functional analysis of human cytomegalovirus polymerase accessory protein. Virus Res. 34: 191-206.
54. Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffing M, Hammerschmidt W. 1999. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 18:3064-3073.
55. Wang Z, Luo F, Li L, Yang L, Hu D, Ma X, Lu Z, Sun L, Cao Y. 2010. STAT3 activation induced by Epstein-Barr virus latent membrane protein1 causes vascular endothelial growth factor expression and cellular invasiveness via JAK3 And ERK signaling. Eur. J. Cancer 46:2996-3006.
56. Punjabi AS, Carroll PA, Chen L, Lagunoff M. 2007. Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J. Virol. 81:2449-2458.
57. Chung YH, Cho NH, Garcia MI, Lee SH, Feng P, Jung JU. 2004. Activation of Stat3 transcription factor by herpesvirus saimiri STP-A oncoprotein. J. Virol. 78:6489-6497.
58. Sen N, Che X, Rajamani J, Zerboni L, Sung P, Ptacek J, Arvin AM. 2012. Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis. Proc. Natl. Acad. Sci. U.S.A. 109:600-605.
59. Ulane CM, Rodriguez JJ, Parisien JP, Horvath CM. 2003. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J. Virol. 77:6385-6393.
60. Valmas C, Grosch MN, Schumann M, Olejnik J, Martinez O, Best SM, Krahling V, Basler CF, Muhlberger E. 2010. Marburg virus evades interferon responses by a mechanism distinct from Ebola virus. PLoS Pathog. 6(1):e1000721. doi:10.1371/journal.ppat.1000721.
61. Munch K, Messerle M, Plachter B, Koszinowski UH. 1992. An acidic region of the 89K murine cytomegalovirus immediate early protein interacts with DNA. J. Gen. Virol. 73:499-506.
62. Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A, Lira SA, Soderberg-Naucler C, Smit MJ. 2010. HCMVencoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci. Signal. 3:ra58. doi:10.1126/scisignal .2001180.
63. Dumortier J, Streblow DN, Moses AV, Jacobs JM, Kreklywich CN, Camp D, Smith RD, Orloff SL, Nelson JA. 2008. Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J. Virol. 82:6524-6535.
64. Le VT, Trilling M, Wilborn M, Hengel H, Zimmermann A. 2008. Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation. J. Gen. Virol. 89:2416-2426.
65. Colberg-Poley AM. 1996. Functional roles of immediate early proteins encoded by the human cytomegalovirus UL36-38, UL115-119, TRS1/ IRS1 and US3 loci. Intervirology 39:350-360.
66. Alvarez-Castelao B, Martin-Guerrero I, Garcia-Orad A, Castano JG. 2009. Cytomegalovirus promoter up-regulation is the major cause of increased protein levels of unstable reporter proteins after treatment of living cells with proteasome inhibitors. J. Biol. Chem. 284:28253-28262.
67. Fehr AR, Yu D. 2011. Human cytomegalovirus early protein pUL21a promotes efficient viral DNA synthesis and the late accumulation of immediate-early transcripts. J. Virol. 85:663-674.
68. Marshall EE, Bierle CJ, Brune W, Geballe AP. 2009. Essential role for either TRS1 or IRS1 in human cytomegalovirus replication. J. Virol. 83: 4112-4120.
69. Nevels M, Brune W, Shenk T. 2004. SUMOylation of the human cytomegalovirus 72-kilodalton IE1 protein facilitates expression of the 86-kilodalton IE2 protein and promotes viral replication. J. Virol. 78:7803-7812.
70. Tran K, Kamil JP, Coen DM, Spector DH. 2010. Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. J. Virol. 84:10832-10843.
71. Johnston PA, Grandis JR. 2011. STAT3 signaling: anticancer strategies and challenges. Mol. Interv. 11:18-26.
72. Ghosh N, Chaki R, Mandal V, Mandal SC. 2010. COX-2 as a target for cancer chemotherapy. Pharmacol. Rep. 62:233-244.
73. Liu DB, Hu GY, Long GX, Qiu H, Mei Q, Hu GQ. 2012. Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation. Acta Pharmacol. Sin. 33: 682-690.
74. Yang F, Van Meter TE, Buettner R, Hedvat M, Liang W, Kowolik CM, Mepani N, Mirosevich J, Nam S, Chen MY, Tye G, Kirschbaum M, Jove R. 2008. Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol. Cancer Ther. 7:3519-3526.
75. Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, Khan Z, Sveinbjornsson B, Fuskevag OM, Segerstrom L, Nordenskjold M, Siesjo P, Kogner P, Johnsen JI, Soderberg-Naucler C. 2011. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J. Clin. Invest. 121:4043-4055.
76. Michaelis M, Paulus C, Loschmann N, Dauth S, Stange E, Doerr HW, Nevels M, Cinatl J, Jr. 2011. The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication. Cell. Mol. Life Sci. 68:1079-1090.