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.
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.
Lan
Ke
K
Department of Microbiology and the Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Kuppers
Daniel A
DA
Robertson
Erle S
ES
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
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
Blood. 2002 Jul 15;100(2):698-700
12091368
Genes Dev. 2002 Aug 1;16(15):1977-89
12154127
EMBO Rep. 2002 Sep;3(9):840-5
12223465
Mayo Clin Proc. 2002 Sep;77(9):941-9
12233927
J Virol. 2002 Nov;76(22):11596-604
12388720
J Virol. 2002 Dec;76(23):12044-54
12414946
J Biol Chem. 2002 Dec 27;277(52):50612-20
12386158
J Virol. 2003 Jan;77(2):1441-51
12502859
Nat Med. 2003 Mar;9(3):300-6
12592400
Cancer Cell. 2003 Feb;3(2):131-43
12620408
J Virol. 2003 Apr;77(7):4261-72
12634383
J Virol. 2003 Jun;77(12):6761-8
12767996
N Engl J Med. 1995 May 4;332(18):1186-91
7700311
J Virol. 1995 May;69(5):3108-16
7707539
J Virol. 1996 May;70(5):3068-74
8627785
Am J Pathol. 1996 Jul;149(1):53-7
8686762
Curr Biol. 1995 Dec 1;5(12):1416-23
8749394
J Virol. 1996 Nov;70(11):8218-23
8892957
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862-7
8962146
J Virol. 1997 Jan;71(1):314-24
8985352
Nihon Rinsho. 1997 Feb;55(2):293-8
9046813
J Biol Chem. 1997 Apr 25;272(17):11336-43
9111040
J Virol. 1997 Aug;71(8):5915-21
9223481
J Clin Invest. 1997 Nov 15;100(10):2606-10
9366576
J Virol. 1999 Dec;73(12):9789-95
10559289
Nature. 1999 Dec 23-30;402(6764):889-94
10622254
J Biol Chem. 2000 Jun 2;275(22):17211-20
10747963
J Virol. 2000 Jul;74(13):6207-12
10846108
J Immunol. 2000 Aug 15;165(4):2077-83
10925292
J Virol. 2000 Sep;74(18):8532-40
10954554
J Virol. 2000 Oct;74(20):9637-45
11000236
Nat Med. 2000 Oct;6(10):1121-7
11017143
J Virol. 2000 Nov;74(21):10187-93
11024147
J Gen Virol. 2000 Dec;81(Pt 12):3043-8
11086135
Dev Biol. 2000 Dec 15;228(2):151-65
11112321
J Virol. 2001 Jan;75(1):458-68
11119614
J Virol. 2001 Apr;75(7):3250-8
11238851
J Virol. 2001 Apr;75(8):3948-59
11264383
Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):517-34
11313009
Blood. 2001 May 15;97(10):3244-50
11342455
Mech Dev. 2001 Jun;104(1-2):3-20
11404076
J Biol Chem. 2001 Jun 22;276(25):22971-8
11313352
J Virol. 2001 Sep;75(17):7882-92
11483733
J Biol Chem. 2001 Aug 17;276(33):31016-22
11425857
J Virol. 2001 Sep;75(18):8761-71
11507221
J Virol. 2001 Oct;75(19):9446-57
11533207
Mol Cell Biol. 2001 Nov;21(22):7761-74
11604511
Cancer. 2001 Dec 15;92(12):3076-84
11753987
Front Biosci. 2002 Feb 1;7:d358-75
11815281
Nature. 1998 Jan 1;391(6662):86-9
9422510
Immunobiology. 1997 Dec;198(1-3):299-306
9442401
J Virol. 1998 Jul;72(7):6034-9
9621066
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10866-71
9724796
J Virol. 1998 Oct;72(10):8309-15
9733875
Mol Cell Biol. 1998 Dec;18(12):7423-31
9819428
Virology. 1998 Dec 20;252(2):304-12
9878608
J Virol. 1999 Mar;73(3):2232-42
9971806
Science. 1999 Apr 23;284(5414):641-4
10213686
Science. 1999 Apr 30;284(5415):770-6
10221902
Trends Microbiol. 1999 May;7(5):196-200
10354594
Adv Virus Res. 1999;52:139-232
10384236
J Virol. 1999 Nov;73(11):9348-61
10516043
J Virol. 2003 Jul;77(14):8019-30
12829841
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8490-5
12832621
J Gen Virol. 2003 Aug;84(Pt 8):1941-9
12867624
J Virol. 2003 Sep;77(17):9451-62
12915560
J Virol. 2003 Sep;77(17):9590-612
12915572
Nat Immunol. 2004 Mar;5(3):247-53
14985712
J Biol Chem. 2004 Apr 16;279(16):16822-31
14742422
J Virol. 2004 Jun;78(12):6585-94
15163750
Nucleic Acids Res. 1994 Mar 25;22(6):965-71
8152928
Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7568-72
8052621
Nucleic Acids Res. 1994 Aug 11;22(15):2938-44
8065905
EMBO J. 1994 Dec 1;13(23):5633-8
7988560
J Virol. 1995 Mar;69(3):1944-50
7853539
Virology. 2001 Dec 20;291(2):241-59
11878894