title: Kaposi's sarcoma-associated herpesvirus-encoded LANA interacts with host KAP1 to facilitate establishment of viral latency.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) typically displays two different phases in its life cycle, the default latent phase and the lytic phase. There is a short period of lytic gene expression in the early stage of KSHV primary infection. The factors involved in the shutdown process of lytic gene expression are poorly identified. It has been shown that the latency-associated nuclear antigen (LANA) encoded by KSHV plays an important role in the establishment of viral latency. In screening, we identified a host protein, Krüppel-associated box domain-associated protein 1 (KAP1), that bound to LANA. We validated the interaction between LANA and KAP1 in vivo and in vitro, as well as their colocalization in the nucleus. We mapped out that LANA interacted with both the N- and C-terminal domains of KAP1. Based on the interface of LANA-KAP1 interaction determined, we proved that LANA recruited KAP1 to the RTA promoter region of the KSHV genome. We revealed that KAP1 was involved in transcriptional repression by LANA. We found multiple cooccupation sites of LANA and KAP1 on the whole KSHV genome by chromatin immunoprecipitation for sequencing (ChIP-seq) and demonstrated that LANA-recruited KAP1 played a critical role in the shutdown of lytic gene expression during the early stage of KSHV primary infection. Taken together, our data suggest that LANA interacts with KAP1 and represses lytic gene expression to facilitate the establishment of KSHV latency.
  
  
  OBJECTIVE
  Our study revealed the mechanism of transcriptional repression by LANA during KSHV primary infection, providing new insights into the process of KSHV latency establishment.
authors.affiliation: Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Deguang
authors.initials: D
authors.lastname: Liang
authors.affiliation: Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China lanke@ips.ac.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
mesh_terms: D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D015534:Trans-Activators; D000076183:Tripartite Motif-Containing Protein 28; D014407:Tumor Cells, Cultured; D014775:Virus Activation / Q000235:genetics; D017735:Virus Latency / Q000502:physiology*
chemical_list: D000956:Antigens, Viral; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; C109540:latency-associated nuclear antigen; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28
references.citation: J Virol. 2012 May;86(10):5752-62
references.pmid: 22419807
references.citation: Mol Cell. 2007 Dec 14;28(5):823-37
references.pmid: 18082607
references.citation: Science. 1999 Apr 23;284(5414):641-4
references.pmid: 10213686
references.citation: Curr Protoc Protein Sci. 2009 Aug;Chapter 19:Unit19.20
references.pmid: 19688738
references.citation: PLoS Pathog. 2013;9(10):e1003673
references.pmid: 24146618
references.citation: J Mol Biol. 2000 Feb 4;295(5):1139-62
references.pmid: 10653693
references.citation: J Virol. 2003 Sep;77(18):9738-49
references.pmid: 12941882
references.citation: J Virol. 2008 Jul;82(13):6734-46
references.pmid: 18417561
references.citation: J Virol. 2010 Apr;84(8):3898-908
references.pmid: 20130056
references.citation: J Gen Virol. 2010 May;91(Pt 5):1138-49
references.pmid: 20089804
references.citation: FEBS Lett. 2006 Jan 9;580(1):93-8
references.pmid: 16364321
references.citation: J Virol. 2013 Jun;87(12):6782-93
references.pmid: 23576503
references.citation: J Virol. 2006 Jun;80(11):5273-82
references.pmid: 16699007
references.citation: Virology. 2007 Aug 1;364(2):317-29
references.pmid: 17434559
references.citation: J Virol. 2005 Mar;79(6):3468-78
references.pmid: 15731241
references.citation: J Biol Chem. 2011 Jul 29;286(30):26267-76
references.pmid: 21652716
references.citation: Virology. 2008 Sep 30;379(2):234-44
references.pmid: 18684478
references.citation: Genes Dev. 2002 Apr 15;16(8):919-32
references.pmid: 11959841
references.citation: Blood. 1995 Aug 15;86(4):1276-80
references.pmid: 7632932
references.citation: PLoS Pathog. 2013;9(11):e1003750
references.pmid: 24278015
references.citation: Nat Med. 2000 Oct;6(10):1121-7
references.pmid: 11017143
references.citation: J Virol. 2002 Nov;76(22):11596-604
references.pmid: 12388720
references.citation: Biochem Biophys Res Commun. 2010 Apr 16;394(4):934-9
references.pmid: 20303334
references.citation: J Virol. 2004 Oct;78(20):11121-9
references.pmid: 15452232
references.citation: J Biol Chem. 2001 Aug 17;276(33):31016-22
references.pmid: 11425857
references.citation: J Biol Chem. 2012 Jun 1;287(23):18937-52
references.pmid: 22496453
references.citation: Virology. 1998 Dec 20;252(2):304-12
references.pmid: 9878608
references.citation: J Virol. 2005 Jun;79(12):7453-65
references.pmid: 15919901
references.citation: J Virol. 2004 Oct;78(19):10348-59
references.pmid: 15367601
references.citation: J Biol Chem. 2012 Feb 17;287(8):5806-18
references.pmid: 22179613
references.citation: J Virol Methods. 2011 Jun;174(1-2):12-21
references.pmid: 21419799
references.citation: J Virol. 2012 May;86(9):4956-69
references.pmid: 22379075
references.citation: Biochem Biophys Res Commun. 2010 Jun 4;396(3):608-13
references.pmid: 20417616
references.citation: Mol Cell Biol. 2011 May;31(9):1833-47
references.pmid: 21343339
references.citation: Blood. 2004 Jan 1;103(1):222-8
references.pmid: 12969971
references.citation: J Virol. 2000 Oct;74(20):9637-45
references.pmid: 11000236
references.citation: Blood. 1996 Oct 1;88(7):2648-54
references.pmid: 8839859
references.citation: Blood. 2001 May 15;97(10):3244-50
references.pmid: 11342455
references.citation: J Virol. 2005 Mar;79(5):3127-38
references.pmid: 15709032
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14554-9
references.pmid: 16983096
references.citation: Genes Dev. 2001 Feb 15;15(4):428-43
references.pmid: 11230151
references.citation: Virology. 2005 Dec 5;343(1):47-64
references.pmid: 16154170
references.citation: J Virol. 2004 Apr;78(7):3601-20
references.pmid: 15016882
references.citation: Adv Virol. 2011;2011:
references.pmid: 21625290
references.citation: Annu Rev Med. 2001;52:453-70
references.pmid: 11160789
references.citation: J Virol. 2004 Sep;78(18):9936-46
references.pmid: 15331727
references.citation: Nat Struct Mol Biol. 2008 Jun;15(6):626-33
references.pmid: 18488044
references.citation: J Virol. 2004 Jun;78(12):6585-94
references.pmid: 15163750
references.citation: N Engl J Med. 1995 May 4;332(18):1186-91
references.pmid: 7700311
references.citation: Cancer Res. 2003 May 1;63(9):2010-5
references.pmid: 12727810
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Virus Genes. 2007 Apr;34(2):127-36
references.pmid: 17143723
references.citation: Nat Methods. 2012 Mar 04;9(4):357-9
references.pmid: 22388286
references.citation: Nat Med. 2003 Mar;9(3):300-6
references.pmid: 12592400
references.citation: J Virol. 1999 Dec;73(12):9789-95
references.pmid: 10559289
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10866-71
references.pmid: 9724796
references.citation: Nat Biotechnol. 2011 Jan;29(1):24-6
references.pmid: 21221095
references.citation: J Virol. 2012 May;86(9):5179-91
references.pmid: 22379092
references.citation: J Virol. 2001 Sep;75(17):7882-92
references.pmid: 11483733
references.citation: J Gen Virol. 1999 Jan;80 ( Pt 1):83-90
references.pmid: 9934688
references.citation: J Virol. 1998 Feb;72(2):1005-12
references.pmid: 9444993
references.citation: PLoS Pathog. 2013;9(10):e1003672
references.pmid: 24146617
references.citation: J Virol. 2012 Feb;86(3):1589-607
references.pmid: 22130534
references.citation: J Virol. 2004 Jul;78(14):7299-310
references.pmid: 15220403
references.citation: PLoS Genet. 2010 Mar 05;6(3):e1000869
references.pmid: 20221260
references.citation: J Virol. 2002 Nov;76(22):11677-87
references.pmid: 12388727
references.citation: J Virol. 2000 Sep;74(18):8532-40
references.pmid: 10954554
references.citation: PLoS Pathog. 2010 Jul 22;6(7):e1001013
references.pmid: 20661424
references.citation: J Virol. 2007 Oct;81(19):10451-9
references.pmid: 17634226
references.citation: Front Microbiol. 2012 Feb 14;3:31
references.pmid: 22347876
references.citation: AIDS. 2000 May 5;14(7):899-902
references.pmid: 10839602
references.citation: Cancer Res. 2009 Jul 15;69(14):5681-9
references.pmid: 19584288
references.citation: J Virol. 2009 Jun;83(11):5574-80
references.pmid: 19279087
references.citation: J Virol. 2011 Sep;85(18):9495-505
references.pmid: 21734034
references.citation: Blood. 2008 May 1;111(9):4731-40
references.pmid: 18199825
references.citation: J Virol. 2006 Aug;80(16):7965-75
references.pmid: 16873253
references.citation: Science. 1994 Dec 16;266(5192):1865-9
references.pmid: 7997879
references.citation: PLoS Pathog. 2013;9(10):e1003640
references.pmid: 24146614
references.citation: Science. 2006 Feb 10;311(5762):856-61
references.pmid: 16469929