title: Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS.
abstract: The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Guigen
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Baca
authors.initials: B
authors.lastname: Chan
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Naira
authors.initials: N
authors.lastname: Samarina
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Bizunesh
authors.initials: B
authors.lastname: Abere
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Weidner-Glunde
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Buch
authors.affiliation: Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pich
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Brinkmann
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; schulz.thomas@mh-hannover.de.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000956:Antigens, Viral; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D020033:Protein Isoforms; C109540:latency-associated nuclear antigen; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: KSHV; cyclic GMP-AMP synthase; cytoplasmic LANA
references.citation: Future Microbiol. 2011 Dec;6(12):1399-413
references.pmid: 22122438
references.citation: Mol Biol Cell. 2002 Aug;13(8):2795-809
references.pmid: 12181347
references.citation: Science. 2013 Apr 12;340(6129):202-7
references.pmid: 23580528
references.citation: J Virol. 2005 Nov;79(22):14457-64
references.pmid: 16254382
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862-7
references.pmid: 8962146
references.citation: J Virol. 2007 Jun;81(11):6134-40
references.pmid: 17360749
references.citation: J Virol. 2013 Nov;87(22):12270-83
references.pmid: 24006437
references.citation: J Virol. 2006 Aug;80(16):8211-24
references.pmid: 16873277
references.citation: Science. 2006 Feb 10;311(5762):856-61
references.pmid: 16469929
references.citation: J Virol. 2007 Aug;81(15):8225-35
references.pmid: 17522213
references.citation: Blood. 2008 May 1;111(9):4731-40
references.pmid: 18199825
references.citation: J Virol Methods. 2015 Jun 1;217:79-86
references.pmid: 25736227
references.citation: PLoS Pathog. 2013 Oct;9(10):e1003751
references.pmid: 24204280
references.citation: J Virol. 2002 Nov;76(22):11596-604
references.pmid: 12388720
references.citation: Science. 2013 Apr 12;340(6129):207-11
references.pmid: 23580529
references.citation: PLoS Pathog. 2014 Feb;10(2):e1003962
references.pmid: 24586165
references.citation: Science. 2013 Feb 15;339(6121):786-91
references.pmid: 23258413
references.citation: Front Microbiol. 2012 Mar 05;3:44
references.pmid: 22403573
references.citation: J Virol. 2002 Nov;76(22):11677-87
references.pmid: 12388727
references.citation: J Virol. 2003 Jun;77(11):6188-96
references.pmid: 12743275
references.citation: Science. 2013 Sep 20;341(6152):1390-4
references.pmid: 23989956
references.citation: J Virol. 2005 Jul;79(13):8493-505
references.pmid: 15956592
references.citation: J Virol. 2010 Mar;84(5):2318-30
references.pmid: 20032179
references.citation: J Clin Invest. 2005 Mar;115(3):642-52
references.pmid: 15765147
references.citation: PLoS One. 2010;5(9). pii: e13076. doi: 10.1371/journal.pone.0013076
references.pmid: 20927329
references.citation: J Virol. 2004 Jun;78(12):6585-94
references.pmid: 15163750
references.citation: Virology. 2008 Sep 30;379(2):234-44
references.pmid: 18684478
references.citation: J Virol. 2011 Aug;85(15):7622-33
references.pmid: 21593163
references.citation: J Virol. 2013 Mar;87(5):2744-55
references.pmid: 23255808
references.citation: PLoS Pathog. 2014 Jul;10(7):e1004253
references.pmid: 25010525
references.citation: Science. 2015 Sep 11;349(6253):1228-32
references.pmid: 26229117
references.citation: Cell Rep. 2013 May 30;3(5):1355-61
references.pmid: 23707065
references.citation: Proc Natl Acad Sci U S A. 2015 May 26;112(21):6694-9
references.pmid: 25947153
references.citation: Immunity. 2015 Feb 17;42(2):332-43
references.pmid: 25692705
references.citation: Mol Cell. 2013 Jul 25;51(2):226-35
references.pmid: 23747010
references.citation: J Virol. 2005 Nov;79(22):14149-60
references.pmid: 16254350
references.citation: Cell Cycle. 2012 Apr 1;11(7):1393-9
references.pmid: 22421142
references.citation: N Engl J Med. 1996 Jul 25;335(4):233-41
references.pmid: 8657239
references.citation: Cell Host Microbe. 2015 Sep 9;18(3):333-44
references.pmid: 26320998
references.citation: J Virol. 2005 Nov;79(21):13618-29
references.pmid: 16227282
references.citation: PLoS Pathog. 2013;9(11):e1003737
references.pmid: 24244164
references.citation: J Virol. 2014 Aug;88(16):9245-59
references.pmid: 24899179
references.citation: J Virol. 2013 Jul;87(14):8004-16
references.pmid: 23678173
references.citation: Science. 2015 Oct 30;350(6260):568-71
references.pmid: 26405230
references.citation: Nat Med. 1996 Aug;2(8):925-8
references.pmid: 8705864
references.citation: Virology. 2004 Aug 1;325(2):225-40
references.pmid: 15246263
references.citation: J Virol. 1997 Aug;71(8):5915-21
references.pmid: 9223481
references.citation: Cell Host Microbe. 2015 May 13;17(5):653-61
references.pmid: 25974304
references.citation: J Virol. 2015 May;89(10):5536-56
references.pmid: 25740990
references.citation: J Clin Invest. 1997 Nov 15;100(10):2606-10
references.pmid: 9366576
references.citation: J Biol Chem. 2002 Jul 26;277(30):27401-11
references.pmid: 12015325
references.citation: J Biol Chem. 2010 Mar 5;285(10):7208-21
references.pmid: 20048166
references.citation: Virology. 2003 Nov 10;316(1):64-74
references.pmid: 14599791
references.citation: J Virol. 2010 Apr;84(8):3898-908
references.pmid: 20130056
references.citation: PLoS Pathog. 2013;9(11):e1003748
references.pmid: 24244169
references.citation: Virology. 2011 Apr 10;412(2):357-65
references.pmid: 21324504
references.citation: Nature. 2014 Jan 30;505(7485):691-5
references.pmid: 24284630
references.citation: J Biol Chem. 2006 Sep 22;281(38):28113-21
references.pmid: 16861237
references.citation: Nature. 2015 Apr 23;520(7548):553-7
references.pmid: 25642965
references.citation: J Virol. 2011 Oct;85(20):10899-904
references.pmid: 21835791
references.citation: Cell. 2013 May 23;153(5):1094-107
references.pmid: 23647843
references.citation: EMBO J. 2014 Dec 17;33(24):2937-46
references.pmid: 25425575
references.citation: J Virol. 2012 Feb;86(3):1883-7
references.pmid: 22090125
references.citation: Nature. 2013 Jun 20;498(7454):380-4
references.pmid: 23722158
references.citation: J Immunol. 2015 Feb 15;194(4):1819-31
references.pmid: 25595793
references.citation: J Virol. 1999 Dec;73(12):9789-95
references.pmid: 10559289
references.citation: J Virol. 2004 Jan;78(1):294-301
references.pmid: 14671111
references.citation: Front Microbiol. 2012 Jan 24;3:7
references.pmid: 22291692
references.citation: Nat Med. 1996 Aug;2(8):918-24
references.pmid: 8705863
references.citation: PLoS Pathog. 2015 Jul;11(7):e1005064
references.pmid: 26218605
references.citation: J Virol. 2006 Jan;80(1):192-200
references.pmid: 16352543
references.citation: J Virol. 2014 May;88(10):5778-87
references.pmid: 24623417
references.citation: PLoS Pathog. 2014 Jan;10(1):e1003863
references.pmid: 24453968
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4342-9
references.pmid: 25271323
references.citation: Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4306-15
references.pmid: 26199418
references.citation: J Biol Chem. 2005 Feb 4;280(5):3862-74
references.pmid: 15525642