title: Kaposi's sarcoma-associated herpesvirus reactivation is regulated by interaction of latency-associated nuclear antigen with recombination signal sequence-binding protein Jkappa, the major downstream effector of the Notch signaling pathway.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the major biological cofactor contributing to development of Kaposi's sarcoma. KSHV establishes a latent infection in human B cells expressing the latency-associated nuclear antigen (LANA), a critical factor in the regulation of viral latency. LANA controls KSHV latent infection through repression of RTA, an activator of many lytic promoters. RTA activates the expression of several lytic viral genes by interacting with recombination signal sequence-binding protein Jkappa (RBP-Jkappa), a transcriptional repressor and the target of the Notch signaling pathway. The recognition that a number of KSHV lytic gene promoters, including RTA, contain RBP-Jkappa binding sites raised the possibility that RBP-Jkappa-mediated repression may be central to the establishment of latency. Here, we tested this hypothesis by examining the regulation of RTA by LANA through binding to RBP-Jkappa. This study demonstrates that LANA physically associates with RBP-Jkappa in vitro and in KSHV-infected cells, with the complex formed capable of binding to RBP-Jkappa cognate sequences. RBP-Jkappa binding sites within the RTA promoter have been found to be critical for LANA-mediated repression. Our study describes a novel mechanism through which LANA maintains KSHV latency by targeting a major downstream effector of the Notch signaling pathway.
authors.affiliation: Department of Microbiology and the Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kuppers
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000956:Antigens, Viral; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation
chemical_list: D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009687:Nuclear Proteins; C497570:RBPJ protein, human; D012333:RNA, Messenger; D012367:RNA, Viral; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; C109540:latency-associated nuclear antigen
references.citation: Blood. 2002 Jul 15;100(2):698-700
references.pmid: 12091368
references.citation: Genes Dev. 2002 Aug 1;16(15):1977-89
references.pmid: 12154127
references.citation: EMBO Rep. 2002 Sep;3(9):840-5
references.pmid: 12223465
references.citation: Mayo Clin Proc. 2002 Sep;77(9):941-9
references.pmid: 12233927
references.citation: J Virol. 2002 Nov;76(22):11596-604
references.pmid: 12388720
references.citation: J Virol. 2002 Dec;76(23):12044-54
references.pmid: 12414946
references.citation: J Biol Chem. 2002 Dec 27;277(52):50612-20
references.pmid: 12386158
references.citation: J Virol. 2003 Jan;77(2):1441-51
references.pmid: 12502859
references.citation: Nat Med. 2003 Mar;9(3):300-6
references.pmid: 12592400
references.citation: Cancer Cell. 2003 Feb;3(2):131-43
references.pmid: 12620408
references.citation: J Virol. 2003 Apr;77(7):4261-72
references.pmid: 12634383
references.citation: J Virol. 2003 Jun;77(12):6761-8
references.pmid: 12767996
references.citation: N Engl J Med. 1995 May 4;332(18):1186-91
references.pmid: 7700311
references.citation: J Virol. 1995 May;69(5):3108-16
references.pmid: 7707539
references.citation: J Virol. 1996 May;70(5):3068-74
references.pmid: 8627785
references.citation: Am J Pathol. 1996 Jul;149(1):53-7
references.pmid: 8686762
references.citation: Curr Biol. 1995 Dec 1;5(12):1416-23
references.pmid: 8749394
references.citation: J Virol. 1996 Nov;70(11):8218-23
references.pmid: 8892957
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862-7
references.pmid: 8962146
references.citation: J Virol. 1997 Jan;71(1):314-24
references.pmid: 8985352
references.citation: Nihon Rinsho. 1997 Feb;55(2):293-8
references.pmid: 9046813
references.citation: J Biol Chem. 1997 Apr 25;272(17):11336-43
references.pmid: 9111040
references.citation: J Virol. 1997 Aug;71(8):5915-21
references.pmid: 9223481
references.citation: J Clin Invest. 1997 Nov 15;100(10):2606-10
references.pmid: 9366576
references.citation: J Virol. 1999 Dec;73(12):9789-95
references.pmid: 10559289
references.citation: Nature. 1999 Dec 23-30;402(6764):889-94
references.pmid: 10622254
references.citation: J Biol Chem. 2000 Jun 2;275(22):17211-20
references.pmid: 10747963
references.citation: J Virol. 2000 Jul;74(13):6207-12
references.pmid: 10846108
references.citation: J Immunol. 2000 Aug 15;165(4):2077-83
references.pmid: 10925292
references.citation: J Virol. 2000 Sep;74(18):8532-40
references.pmid: 10954554
references.citation: J Virol. 2000 Oct;74(20):9637-45
references.pmid: 11000236
references.citation: Nat Med. 2000 Oct;6(10):1121-7
references.pmid: 11017143
references.citation: J Virol. 2000 Nov;74(21):10187-93
references.pmid: 11024147
references.citation: J Gen Virol. 2000 Dec;81(Pt 12):3043-8
references.pmid: 11086135
references.citation: Dev Biol. 2000 Dec 15;228(2):151-65
references.pmid: 11112321
references.citation: J Virol. 2001 Jan;75(1):458-68
references.pmid: 11119614
references.citation: J Virol. 2001 Apr;75(7):3250-8
references.pmid: 11238851
references.citation: J Virol. 2001 Apr;75(8):3948-59
references.pmid: 11264383
references.citation: Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):517-34
references.pmid: 11313009
references.citation: Blood. 2001 May 15;97(10):3244-50
references.pmid: 11342455
references.citation: Mech Dev. 2001 Jun;104(1-2):3-20
references.pmid: 11404076
references.citation: J Biol Chem. 2001 Jun 22;276(25):22971-8
references.pmid: 11313352
references.citation: J Virol. 2001 Sep;75(17):7882-92
references.pmid: 11483733
references.citation: J Biol Chem. 2001 Aug 17;276(33):31016-22
references.pmid: 11425857
references.citation: J Virol. 2001 Sep;75(18):8761-71
references.pmid: 11507221
references.citation: J Virol. 2001 Oct;75(19):9446-57
references.pmid: 11533207
references.citation: Mol Cell Biol. 2001 Nov;21(22):7761-74
references.pmid: 11604511
references.citation: Cancer. 2001 Dec 15;92(12):3076-84
references.pmid: 11753987
references.citation: Front Biosci. 2002 Feb 1;7:d358-75
references.pmid: 11815281
references.citation: Nature. 1998 Jan 1;391(6662):86-9
references.pmid: 9422510
references.citation: Immunobiology. 1997 Dec;198(1-3):299-306
references.pmid: 9442401
references.citation: J Virol. 1998 Jul;72(7):6034-9
references.pmid: 9621066
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10866-71
references.pmid: 9724796
references.citation: J Virol. 1998 Oct;72(10):8309-15
references.pmid: 9733875
references.citation: Mol Cell Biol. 1998 Dec;18(12):7423-31
references.pmid: 9819428
references.citation: Virology. 1998 Dec 20;252(2):304-12
references.pmid: 9878608
references.citation: J Virol. 1999 Mar;73(3):2232-42
references.pmid: 9971806
references.citation: Science. 1999 Apr 23;284(5414):641-4
references.pmid: 10213686
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: Trends Microbiol. 1999 May;7(5):196-200
references.pmid: 10354594
references.citation: Adv Virus Res. 1999;52:139-232
references.pmid: 10384236
references.citation: J Virol. 1999 Nov;73(11):9348-61
references.pmid: 10516043
references.citation: J Virol. 2003 Jul;77(14):8019-30
references.pmid: 12829841
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8490-5
references.pmid: 12832621
references.citation: J Gen Virol. 2003 Aug;84(Pt 8):1941-9
references.pmid: 12867624
references.citation: J Virol. 2003 Sep;77(17):9451-62
references.pmid: 12915560
references.citation: J Virol. 2003 Sep;77(17):9590-612
references.pmid: 12915572
references.citation: Nat Immunol. 2004 Mar;5(3):247-53
references.pmid: 14985712
references.citation: J Biol Chem. 2004 Apr 16;279(16):16822-31
references.pmid: 14742422
references.citation: J Virol. 2004 Jun;78(12):6585-94
references.pmid: 15163750
references.citation: Nucleic Acids Res. 1994 Mar 25;22(6):965-71
references.pmid: 8152928
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7568-72
references.pmid: 8052621
references.citation: Nucleic Acids Res. 1994 Aug 11;22(15):2938-44
references.pmid: 8065905
references.citation: EMBO J. 1994 Dec 1;13(23):5633-8
references.pmid: 7988560
references.citation: J Virol. 1995 Mar;69(3):1944-50
references.pmid: 7853539
references.citation: Virology. 2001 Dec 20;291(2):241-59
references.pmid: 11878894