Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II
Autoři:
Ming Li aff001; Christopher B. Ball aff002; Geoffrey Collins aff002; Qiaolin Hu aff001; Donal S. Luse aff003; David H. Price aff002; Jeffery L. Meier aff001
Působiště autorů:
Departments of Internal Medicine and Epidemiology, University of Iowa and Iowa City Veterans Affairs Health Care System, Iowa City, IA, United States of America
aff001; Department of Biochemistry, University of Iowa, Iowa City, IA, United States of America
aff002; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America
aff003
Vyšlo v časopise:
Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II. PLoS Pathog 16(4): e1008402. doi:10.1371/journal.ppat.1008402
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.ppat.1008402
Souhrn
Herpesvirus late promoters activate gene expression after viral DNA synthesis has begun. Alphaherpesviruses utilize a viral immediate-early protein to do this, whereas beta- and gammaherpesviruses primarily use a 6-member set of viral late-acting transcription factors (LTF) that are drawn to a TATT sequence in the late promoter. The betaherpesvirus, human cytomegalovirus (HCMV), produces three immediate-early 2 protein isoforms, IE2-86, IE2-60, IE2-40, late in infection, but whether they activate late viral promoters is unknown. Here, we quickly degrade the IE2 proteins in late infection using dTag methodology and analyze effects on transcription using customized PRO-Seq and computational methods combined with multiple validation methods. We discover that the IE2 proteins selectively drive RNA Pol II transcription initiation at a subset of viral early-late and late promoters common to different HCMV strains, but do not substantially affect Pol II transcription of the 9,942 expressed host genes. Most of the IE2-activated viral late infection promoters lack the TATT sequence bound by the HCMV UL87-encoded LTF. The HCMV TATT-binding protein is not mechanistically involved in late RNA expression from the IE2-activated TATT-less UL83 (pp65) promoter, as it is for the TATT-containing UL82 (pp71) promoter. While antecedent viral DNA synthesis is necessary for transcription from the late infection viral promoters, continued viral DNA synthesis is unnecessary. We conclude that in late infection the IE2 proteins target a distinct subset of HCMV early-late and late promoters for transcription initiation by RNA Pol II. Commencement of viral DNA replication renders the HCMV genome late promoters susceptible to late-acting viral transcription factors.
Klíčová slova:
Cytomegalovirus infection – DNA replication – DNA transcription – DNA-binding proteins – Human cytomegalovirus – Polymerase chain reaction – Transcription factors – Viral genomics
Zdroje
1. Stinski MF, Thomsen DR, Stenberg RM, Goldstein LC. Organization and expression of the immediate early genes of human cytomegalovirus. J Virol. 1983;46:1–14. 6298447
2. Stenberg RM, Witte PR, Stinski MF. Multiple spliced and unspliced transcripts from human cytomegalovirus immediate-early region 2 and evidence for a common initiation site within immediate-early region 1. J Virol. 1985;56(3):665–75. 2999423
3. Stenberg RM, Depto AS, Fortney J, Nelson JA. Regulated expression of early and late RNAs and proteins from the human cytomegalovirus immediate-early gene region. J Virol. 1989;63(6):2699–708. 2542583
4. Hermiston TW, Malone CL, Witte PR, Stinski MF. Identification and characterization of the human cytomegalovirus immediate-early region 2 gene that stimulates gene expression from an inducible promoter. J Virol. 1987;61(10):3214–21. 3041043
5. Chang C-P, Malone CL, Stinski MF. A human cytomegalovirus early gene has three inducible promoters that are regulated differentially at various times after infection. J Virol. 1989;63:281–90. 2535734
6. Klucher KM, Spector DH. The human cytomegalovirus 2.7-kilobase RNA promoter contains a functional binding site for the adenovirus major late transcription factor. J Virol. 1990;64:4189–98. 2166813
7. Marchini A, Liu H, Zhu H. Human cytomegalovirus with IE-2 deleted fails to express early lytic genes. J Virol. 2001;75:1870–8. doi: 10.1128/JVI.75.4.1870-1878.2001 11160686
8. Anderson KP, Fox MC, Brown-Driver V, Martin MM, Azad RF. Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemotherap. 1996;40(9):2004–11.
9. Meier JL, Stinski MF. Major immediate-early enhancer and its gene products. In: Reddehase MJ, editor. Cytomegaloviruses: Molecular Biology and Immunology. Norfolk, U. K.: Caister Academic Press; 2006. p. 151–66.
10. Lukac DM, Harel NY, Tanese N, Alwine JC. TAF-like functions of human cytomegalovirus immediate-early proteins. J Virol. 1997;71:7227–39. 9311796
11. Kim ET, Kim YE, Huh YH, Ahn JH. Role of noncovalent SUMO binding by the human cytomegalovirus IE2 transactivator in lytic growth. J Virol. 2010;84(16):8111–23. doi: 10.1128/JVI.00459-10 20519406
12. Huang L, Stinski MF. Binding of cellular repressor protein or the IE2 protein to a cis-acting negative regulatory element upstream of a human cytomegalovirus early promoter. J Virol. 1995;69(12):7612–21. 7494269
13. Arlt H, Lang D, Gebert S, Stamminger T. Identification of binding sites for the 86-kilodalton IE2 protein of human cytomegalovirus within an IE2-responsive viral early promoter. J Virol. 1994;68(7):41117–4125.
14. Klucher KM, Sommer M, Kadonaga JT, Spector DH. In vivo and in vitro analysis of transcriptional activation mediated by the human cytomegalovirus major immediate-early proteins. Mol Cell Biol. 1993;13:1238–50. doi: 10.1128/mcb.13.2.1238 8423789
15. Lee SB, Lee CF, Ou DS, Dulal K, Chang LH, Ma CH, et al. Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2. Cell Res. 2011;21(8):1230–47. doi: 10.1038/cr.2011.53 21445097
16. Kim JE, Kim YE, Stinski MF, Ahn JH, Song YJ. Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-β Induction. Front Microbiol. 2018;26(9).
17. Macias MP, Stinski MF. An in vitro system for human cytomegalovirus immediate early 2 protein (IE2)-mediated site-dependent repression of transcription and direct binding of IE2 to the major immediate early promoter. Proc Natl Acad Sci USA. 1993;90:707–11. doi: 10.1073/pnas.90.2.707 8380646
18. Chiou CJ, Zong J, Waheed I, Hayward GS. Identification and mapping of dimerization and DNA-binding domains in the C terminus of the IE2 regulatory protein of human cytomegalovirus. J Virol. 1993;67(10):6201–14. 8396676
19. Pizzorno MC, Hayward GS. The IE2 gene products of human cytomegalovirus specifically down-regulate expression from the major immediate-early promoter through a target sequence located near the cap site. J Virol. 1990;64:6154–65. 2173785
20. Cherrington JM, Khoury EL, Mocarski ES. Human cytomegalovirus ie2 negatively regulates alpha gene expression via a short target sequence near the transcription start site. J Virol. 1991;65(2):887–96. 1846203
21. Liu B, Hermiston TW, Stinski MF. A cis-acting element in the major immediate-early (IE) promoter of human cytomegalovirus is required for negative regulation by IE2. J Virol. 1991;65(2):897–903. 1846204
22. Dremel SE, DeLuca NA. Genome replication affects transcription factor binding mediating the cascade of herpes simplex virus transcription. Proc Natl Acad Sci U S A. 2019;116(9):3734–9. doi: 10.1073/pnas.1818463116 30808759
23. Kim D-B, Zabierowski S, Deluca N. The initiator element in a herpes simplex virus type 1 late-gene promoter enhances activation of ICP4, resulting in abundant late-gene expression. J Virol. 2002;76:1548–58. doi: 10.1128/JVI.76.4.1548-1558.2002 11799149
24. Mavomara-Nazos P, Roizman B. Dilenation of regulatory domains of early (beta) and late (gamma 2) genes by construction of chimeric genes expressed in herpes simplex virus 1 genomes. Proc Natl Acad Sci U S A. 1989;86:4071–5. doi: 10.1073/pnas.86.11.4071 2542962
25. Isomura H, Stinski MF, Murata T, Yamashita Y, Kanda T, Toyokuni S, et al. The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication. J Virol. 2011;85(13):6629–44. doi: 10.1128/JVI.00384-11 21507978
26. Davis ZH, Verschueren E, Jang GM, Kleffman K, Johnson JR, Park J, et al. Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell. 2015;57(2):349–60. doi: 10.1016/j.molcel.2014.11.026 25544563
27. Aubry V, Mure F, Mariamé B, Deschamps T, Wyrwicz LS, Manet E, et al. Epstein-Barr virus late gene transcription depends on the assembly of a virus-specific preinitiation complex. J Virol. 2014;88(21):12825–38. doi: 10.1128/JVI.02139-14 25165108
28. Perng YC, Qian Z, Fehr AR, Xuan B, Yu D. The human cytomegalovirus gene UL79 is required for the accumulation of late viral transcripts. J Virol. 2011;885(10):4841–52.
29. Omoto S, Mocarski ES. Transcription of true late (γ2) cytomegalovirus genes requires UL92 function that is conserved among beta- and gammaherpesviruses. J Virol. 2014;88(1):120–30. doi: 10.1128/JVI.02983-13 24131715
30. Omoto S, Mocarski ES. Cytomegalovirus UL91 is essential for transcription of viral true late (γ2) genes. J Virol. 2013;87(15):8651–64. doi: 10.1128/JVI.01052-13 23720731
31. Puchtler E, Stamminger T. An inducible promoter mediates abudant expression from the immediate-early 2 gene region of the human cytomegalovirus at late times after infection. J Virol. 1991;65(11):6301–6. 1656096
32. White EA, Del Rosario CJ, Sanders RL, Spector DH. The IE2 60-kilodalton and 40-kilodalton proteins are dispensable for human cytomegalovirus replication but are required for efficient delayed early and late gene expression and production of infectious virus. J Virol. 2006;81(6):2573–83.
33. Parida M, Nilson KA, Li M, Ball CBHA, Fuchs HA, Lawson CK, et al. Nucleotide resolution comparison of transcription of human cytomegalovirus and host genomes reveals universal use of RNA polymerase II elongation control driven by dissimilar core promoter elements. MBio. 2019;10:1–20. 30755505
34. Plachter B, Britt W, Vornhagen R, Stamminger T, Jahn G. Analysis of proteins encoded by IE regions 1 and 2 of human cytomegalovirus using monoclonal antibodies generated against recombinant antigens. Virology. 1993;193:642–52. doi: 10.1006/viro.1993.1172 7681609
35. Jenkins DE, Martens CL, Mocarski ES. Human cytomegalovirus late protein encoded by ie2: a trans-activator as well as a repressor of gene expression. J Gen Virol 1994;75:2337–48. doi: 10.1099/0022-1317-75-9-2337 8077932
36. Reuter N, Reichel A, Stilp A-C, Scherer M, Stamminger T. SUMOylation of IE2p86 is required for efficient autorepression of the human cytomegalovirus major immediate-early promoter. J Gen Virol. 2018;99:369–78. doi: 10.1099/jgv.0.001021 29458530
37. Sanders RL, Clark CL, Morello C, Spector DH. 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. 2008;82:7059–77. doi: 10.1128/JVI.00675-08 18463148
38. White EA, Clark CL, Sanchez V, Spector DH. Small internal deletions in the human cytomegalovirus IE2 gene result in nonviable recombinant viruses with differential defects in viral gene expression. J Virol. 2004;78:1817–30. doi: 10.1128/JVI.78.4.1817-1830.2004 14747546
39. Sanders RL, Spector DA. Human cytomegalovirus IE2 86 and IE2 40 proteins differentially regulate UL84 protein expression posttranscriptionally in the absence of other viral gene products. J Virol. 2010;84:5158–70. doi: 10.1128/JVI.00090-10 20200242
40. Kwak H, Fuda NJ, Core LJ, Lis JT. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science. 2013;339(6122):950–3. doi: 10.1126/science.1229386 23430654
41. Core LJ, Waterfall JJ, Lis JT. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science. 2008;322(5909):1845–8. doi: 10.1126/science.1162228 19056941
42. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–8. doi: 10.1126/science.aab1433 25999370
43. Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, et al. The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol. 2018;14(5):431–41. doi: 10.1038/s41589-018-0021-8 29581585
44. Nilson KA, Lawson CK, Mullen NJ, Ball CB, Spector BM, Meier JL, et al. Oxidative stress rapidly stabilizes promoter-proximal paused Pol II across the human genome. Nucleic Acids Res. 2017;45(19):11088–105. doi: 10.1093/nar/gkx724 28977633
45. Depto AS, Stenberg RM. Regulated expression of the human cytomegalovirus pp65 gene: octomer sequence in the promoter is requierd for activation by viral gene products. J Virol. 1989;63:1232–8. 2536831
46. Ruger B, Klages S, Birgitt W, Albrecht J, Fleckenstein B, Tomlinson P, et al. Primary structure and transcription of the genes coding for the two virion phosphoproteins pp65 and pp7l of human cytomegalovirus. J Virol. 1987;61:446–53. 3027374
47. Stern-Ginossar N, Weisburd B, Michalski A, Le VT, Hein MY, Huang SX, et al. Decoding human cytomegalovirus. Science. 2012;338:1088–93. doi: 10.1126/science.1227919 23180859
48. Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow D, Stanton RJ, et al. Quantitative temporal viromics: an approach to investigate host-pathogen interaction. Cell. 2014;157(6):1460–72. doi: 10.1016/j.cell.2014.04.028 24906157
49. He SY, Xu L, Huang ES. Characterization of human cytomegalovirus UL84 early geme and identification of its putative protein product. J Virol. 1992;66:1098–108. 1309892
50. Adam BL, Jervey TY, Kohler CP, Wright GL, Nelson JA, Stenberg RM. The human cytomegalovirus UL98 gene transcription unit overlaps with the pp28 true late gene (UL99) and encode a 58-kilodalton early protein. J Virol. 1995;69:5304–10. 7636973
51. Stinski MF, Petrik DT. Functional roles of the human cytomegalovirus essential IE86 protein. In: Shenk T, Stinski MF, editors. Human Cytomegalovirus Current Topics in Microbiology and Immunology 325. Berlin Heidelberg: Springer-Verlag; 2008. p. 133–52.
52. McKenzie J, Lopez-Giraldez F, Delecluse H-J, Walsh A, El-Guindy A. The Epstein-Barr virus immunoevasins BCRF1 and BPLF1 are expressed by a mechanism independent of the canonical late preinitiation complex. PLoS Pathog. 2016;12(11):e1006008. doi: 10.1371/journal.ppat.1006008 27855219
53. Djavadian R, Hayes M, Johannsen E. CAGE-seq analysis of Epstein-Barr virus lytic gene transcription: 3 kinetic classes from 2 mechanisms. PLoS Pathog. 2018;14(6).
54. Lurain NS, Fox AM, Lichy HM, Bhorade SM, Ware CF, Huang DD, et al. Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts. Virology Journal. 2006;3:4. doi: 10.1186/1743-422X-3-4 16409621
55. Huang L, Stinski MF. Binding of cellular repressor protein or the IE2 protein to a cis-acting negative regulatory element upstream of a human cytomegalovirus early promoter. J Virol. 1995;69(12):7612–21. 7494269
56. Rodems SM, Clark CL, Spector DH. Separate DNA elements containing ATF/CREB and IE86 binding sites differentially regulate the human cytomegalovirus UL112-113 promoter at early and late times in the infection. J Virol. 1998;72:2697–707. 9525587
57. Nandakumar D, Glaunsinger BA. An integrative approach identifies direct targets of the late viral transcription complex and an expanded promoter recognition motif in Kapos’s sarcoma-associated herpesvirus. PLoS Pathog. 2019;15(5):e1007774. doi: 10.1371/journal.ppat.1007774 31095645
58. Du G, Stinski MF. Interaction network of proteins associated with human cytomegalovirus IE2-p86 protein during infection: a proteomic analysis. PLoS One. 2013;8:e81583. doi: 10.1371/journal.pone.0081583 24358118
59. Gibeault RL, Conn KL, Bildersheim MD, Schang LM. An essential viral transcription activator modulates chromatin dynamics. PLoS Pathog. 2016;12:e1005842. doi: 10.1371/journal.ppat.1005842 27575707
60. O” Conner CM, Murphy EA. A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J Virol. 2012;86(18):9854–65. doi: 10.1128/JVI.01278-12 22761372
61. Warming S, Costantino N, Court DL, Jenkins NA, Copeland NG. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Research 2005;30:e36.
62. Meier JL. Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: Role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator. J Virol. 2001;75:1581–93. doi: 10.1128/JVI.75.4.1581-1593.2001 11160656
63. Yuan J, M. L, Torres YR, Galle CS, Meier JL. Differentiation-coupled induction of human cytomegalovirus replication by union of the major enhancer retinoic Acid, cyclic AMP, and NF-κB response elements. J Virol. 2015;89:12284–98. doi: 10.1128/JVI.00965-15 26423948
64. Meier JL, Stinski MF. Effect of a modulator deletion on transcription of the human cytomegalovirus major immediate-early genes in infected undifferentiated and differentiated cells. J Virol. 1997;71:1246–55. 8995648
65. Yuan J, Liu X, Wu AW, McGonagill PW, Keller MJ, Galle CS, et al. Breaking human cytomegalovirus major immediate-early gene silence by vasoactive intestinal peptide stimulation of the protein kinase A-CREB-TORC2 signaling cascade in human pluripotent embryonal NTera2 cells. J Virol. 2009;83:6391–401. doi: 10.1128/JVI.00061-09 19369332
66. Bradley AJ, Lurain NS, Ghazal P, Trivedi U, Cunningham C, Baluchova K, et al. High-throughput sequence analysis of variants of human cytomegalovirus strains Towne and AD169. J Gen Virol. 2009;90:2375–80. doi: 10.1099/vir.0.013250-0 19553388
67. Tomasec P, Wang EC, Davison AJ, Vojtesek B, Armstrong M, Griffin C, et al. Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nat Immunol. 2005;6:181–8. doi: 10.1038/ni1156 15640804
68. Quinalan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26(6):841–2. doi: 10.1093/bioinformatics/btq033 20110278
69. Ball CB, Nilson KA, Price DH. Use of the nuclear walk-on methodology to determine sites of RNA polymerase II initiation and pausing and quantify of nascent RNAs in cells. Methods 2019;S1046–2023(18).
70. Haeussler M, Zweig AS, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, et al. The UCSC Genome Browser database: 2019 update Nucleic Acids Res. 2019;47:D853–8. doi: 10.1093/nar/gky1095 30407534
71. Raney BJ, Dreszer TR, Barber GP, Clawson H, Fujita PA, Wang T, et al. Track data hubs enable visualization of user-defined genome-wide annotations on the UCSC Genome Browser. Bioinformatics. 2014;30(7):1003–5. doi: 10.1093/bioinformatics/btt637 24227676
Článek vyšel v časopise
PLOS Pathogens
2020 Číslo 4
- Jak a kdy u celiakie začíná reakce na lepek? Možnou odpověď poodkryla čerstvá kanadská studie
- Infekce se v Americe po příjezdu Kolumba šířily nesrovnatelně déle, než se traduje
- Jak může lékárník přispět ke zvýšení bezpečnosti terapie kortikosteroidy a zbavit pacienty obav z jejich nežádoucích účinků?
- Budou nanoléčiva lépe cílit na některé onkologické nemoci?
- Prof. Jan Škrha: Metformin je bezpečný, ale je třeba jej bezpečně užívat a léčbu kontrolovat
Nejčtenější v tomto čísle
- Battling brain-eating amoeba: Enigmas surrounding immunity to Naegleria fowleri
- Genetic interaction analysis comes to the diploid human pathogen Candida albicans
- Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II
- Drosophila as a model for the gut microbiome