title: Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters.
abstract: The four Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded interferon (IFN) regulatory factor homologues (vIRF1 to vIRF4) are used to counter innate immune defenses and suppress p53. The vIRF genes are arranged in tandem but differ in function and expression. In KSHV-infected effusion lymphoma lines, K10.5/vIRF3 and K11/vIRF2 mRNAs are readily detected during latency, whereas K9/vIRF1 and K10/vIRF4 mRNAs are upregulated during reactivation. Here we show that the K10/vIRF4 promoter responds to the lytic switch protein RTA in KSHV-infected cells but is essentially unresponsive in uninfected cells. Coexpression of RTA with vIRF4 is sufficient to restore regulation, a property not shared by other vIRFs. The K9/vIRF1 promoter behaves similarly, and production of infectious virus is enhanced by the presence of vIRF4. Synergy requires the DNA-binding domain (DBD) and C-terminal IRF homology regions of vIRF4. Mutations of arginine residues within the putative DNA recognition helix of vIRF4 or the invariant cysteines of the adjacent CxxC motif abolish cooperation with RTA, in the latter case by preventing self-association. The oligomerization and transactivation functions of RTA are also essential for synergy. The K10/vIRF4 promoter contains two transcription start sites (TSSs), and a 105-bp fragment containing the proximal promoter is responsive to vIRF4/RTA. Binding of a cellular factor(s) to this fragment is altered when both viral proteins are present, suggesting a possible mechanism for transcriptional synergy. Reliance on coregulators encoded by either the host or viral genome provides an elegant strategy for expanding the regulatory potential of a master regulator, such as RTA.
authors.affiliation: Department of Microbiology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Xi
authors.forename: Linda M
authors.initials: LM
authors.lastname: Persson
authors.forename: Michael W
authors.initials: MW
authors.lastname: O'Brien
authors.forename: Ian
authors.initials: I
authors.lastname: Mohr
authors.forename: Angus C
authors.initials: AC
authors.lastname: Wilson
mesh_terms: D020816:Amino Acid Motifs; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D050835:Interferon Regulatory Factors; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; C413486:viral interferon regulatory factors
references.citation: J Biol Chem. 2009 Aug 28;284(35):23272-85
references.pmid: 19553679
references.citation: J Virol. 2000 Sep;74(18):8623-34
references.pmid: 10954564
references.citation: J Virol. 2001 Jan;75(1):429-38
references.pmid: 11119611
references.citation: J Virol. 2004 Oct;78(19):10657-73
references.pmid: 15367633
references.citation: Oncogene. 1997 Oct 16;15(16):1979-85
references.pmid: 9365244
references.citation: J Virol. 2001 Aug;75(15):6786-99
references.pmid: 11435557
references.citation: J Virol. 1998 Jan;72(1):701-7
references.pmid: 9420276
references.citation: J Virol. 2004 Jul;78(13):6818-26
references.pmid: 15194757
references.citation: J Virol. 2002 Dec;76(23):12044-54
references.pmid: 12414946
references.citation: J Virol. 2010 Feb;84(3):1334-47
references.pmid: 19906914
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W321-6
references.pmid: 15215403
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862-7
references.pmid: 8962146
references.citation: Mol Cell Biol. 2000 Sep;20(18):6721-30
references.pmid: 10958670
references.citation: J Virol. 2008 Nov;82(21):10709-23
references.pmid: 18715905
references.citation: Virology. 2008 Oct 25;380(2):264-75
references.pmid: 18786687
references.citation: J Virol. 2005 Nov;79(22):14457-64
references.pmid: 16254382
references.citation: J Virol. 2001 Aug;75(15):6894-900
references.pmid: 11435569
references.citation: Nat Rev Immunol. 2006 Sep;6(9):644-58
references.pmid: 16932750
references.citation: J Virol. 2006 Dec;80(24):11968-81
references.pmid: 17020939
references.citation: EMBO J. 1999 Sep 15;18(18):5028-41
references.pmid: 10487755
references.citation: Virology. 2008 Sep 30;379(2):234-44
references.pmid: 18684478
references.citation: J Virol. 2003 Jan;77(1):600-23
references.pmid: 12477864
references.citation: J Virol. 2005 Jul;79(14):8750-63
references.pmid: 15994769
references.citation: J Virol. 2000 Apr;74(7):3388-98
references.pmid: 10708456
references.citation: J Virol. 2001 Jan;75(2):891-902
references.pmid: 11134302
references.citation: J Virol. 2005 Jul;79(13):8493-505
references.pmid: 15956592
references.citation: J Virol. 2007 Nov;81(22):12680-4
references.pmid: 17855527
references.citation: J Virol. 2001 Jul;75(13):6193-8
references.pmid: 11390621
references.citation: J Interferon Cytokine Res. 2009 Sep;29(9):621-7
references.pmid: 19715458
references.citation: J Virol Methods. 2011 Jun;174(1-2):12-21
references.pmid: 21419799
references.citation: Cell Signal. 2010 Jun;22(6):883-7
references.pmid: 20043992
references.citation: Curr Top Microbiol Immunol. 2007;312:185-209
references.pmid: 17089798
references.citation: Mol Cell Biol. 2000 Nov;20(21):8254-63
references.pmid: 11027294
references.citation: Virology. 2006 Aug 15;352(1):100-9
references.pmid: 16716377
references.citation: J Gen Virol. 2003 Jun;84(Pt 6):1471-1483
references.pmid: 12771416
references.citation: J Clin Invest. 2010 Apr;120(4):939-49
references.pmid: 20364091
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Virology. 2009 Apr 25;387(1):76-88
references.pmid: 19269659
references.citation: J Virol. 2005 May;79(9):5640-52
references.pmid: 15827179
references.citation: J Virol. 2006 Mar;80(5):2257-66
references.pmid: 16474133
references.citation: J Virol. 2003 Sep;77(17):9590-612
references.pmid: 12915572
references.citation: EMBO J. 1998 Nov 16;17(22):6660-9
references.pmid: 9822609
references.citation: Annu Rev Immunol. 2008;26:535-84
references.pmid: 18303999
references.citation: PLoS One. 2007 Oct 24;2(10):e1067
references.pmid: 17957251
references.citation: J Virol. 2007 Jun;81(11):5788-806
references.pmid: 17392367
references.citation: Virology. 2009 Apr 10;386(2):290-302
references.pmid: 19233445
references.citation: J Gen Virol. 2003 Feb;84(Pt 2):329-336
references.pmid: 12560564
references.citation: Virology. 2000 Apr 10;269(2):335-44
references.pmid: 10753712
references.citation: J Virol. 2010 Dec;84(23):12255-64
references.pmid: 20861242
references.citation: Blood. 2008 Jan 1;111(1):320-7
references.pmid: 17890449
references.citation: J Virol. 2009 Jul;83(13):6739-47
references.pmid: 19369353
references.citation: Virology. 2010 Feb 20;397(2):311-21
references.pmid: 19969319
references.citation: J Biol Chem. 2002 Nov 15;277(46):44292-9
references.pmid: 12235138
references.citation: J Virol. 2000 Sep;74(18):8532-40
references.pmid: 10954554
references.citation: J Virol. 1999 Sep;73(9):7334-42
references.pmid: 10438822
references.citation: J Virol. 2001 Aug;75(16):7572-82
references.pmid: 11462029
references.citation: Cytokine Growth Factor Rev. 2001 Jun-Sep;12(2-3):245-57
references.pmid: 11325605