title: Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV.
abstract: The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an important cause of morbidity and mortality in immunocompromised patients. KSHV interaction with the cell membrane triggers activation of specific intracellular signal transduction pathways to facilitate virus entry, nuclear trafficking, and ultimately viral oncogene expression. Extracellular heat shock protein 90 localizes to the cell surface (csHsp90) and facilitates signal transduction in cancer cell lines, but whether csHsp90 assists in the coordination of KSHV gene expression through these or other mechanisms is unknown. Using a recently characterized non-permeable inhibitor specifically targeting csHsp90 and Hsp90-specific antibodies, we show that csHsp90 inhibition suppresses KSHV gene expression during de novo infection, and that this effect is mediated largely through the inhibition of mitogen-activated protein kinase (MAPK) activation by KSHV. Moreover, we show that targeting csHsp90 reduces constitutive MAPK expression and the release of infectious viral particles by patient-derived, KSHV-infected primary effusion lymphoma cells. These data suggest that csHsp90 serves as an important co-factor for KSHV-initiated MAPK activation and provide proof-of-concept for the potential benefit of targeting csHsp90 for the treatment or prevention of KSHV-associated illnesses.
authors.affiliation: Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.forename: Michael
authors.initials: M
authors.lastname: DeFee
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Isaacs
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
mesh_terms: D015967:Gene Expression Regulation, Viral; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008223:Lymphoma / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000821:virology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D020928:Mitogen-Activated Protein Kinases
references.citation: J Clin Oncol. 2005 Feb 10;23(5):982-9
references.pmid: 15572730
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4546-51
references.pmid: 10200299
references.citation: Nat Immunol. 2001 Apr;2(4):338-45
references.pmid: 11276205
references.citation: Cancer. 2006 Nov 1;107(9):2282-90
references.pmid: 16998933
references.citation: J Virol. 2004 Apr;78(8):4207-23
references.pmid: 15047836
references.citation: J Biol Chem. 2004 May 21;279(21):22483-9
references.pmid: 15004035
references.citation: Cancer Cell. 2006 Aug;10(2):133-43
references.pmid: 16904612
references.citation: J Infect Dis. 2008 Jul 1;198(1):23-30
references.pmid: 18491970
references.citation: N Engl J Med. 2008 Jan 31;358(5):535-6; author reply 536
references.pmid: 18234764
references.citation: J Virol. 2002 Mar;76(6):2634-40
references.pmid: 11861829
references.citation: Science. 1994 Dec 16;266(5192):1865-9
references.pmid: 7997879
references.citation: Virology. 2007 May 25;362(1):109-19
references.pmid: 17258257
references.citation: Cell Microbiol. 2003 Mar;5(3):165-74
references.pmid: 12614460
references.citation: J Virol. 2005 Jun;79(11):7255-61
references.pmid: 15890964
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):584-90
references.pmid: 16428504
references.citation: Antivir Chem Chemother. 2005;16(2):135-46
references.pmid: 15889536
references.citation: J Gen Virol. 2006 May;87(Pt 5):1139-1144
references.pmid: 16603514
references.citation: EMBO J. 2006 Oct 18;25(20):5015-25
references.pmid: 17024179
references.citation: J Virol. 1997 Jan;71(1):715-9
references.pmid: 8985403
references.citation: J Virol. 2006 Feb;80(3):1167-80
references.pmid: 16414994
references.citation: J Infect Dis. 2002 Jun 15;185(12):1736-44
references.pmid: 12085319
references.citation: Virology. 2008 Sep 30;379(2):234-44
references.pmid: 18684478
references.citation: Mol Biol Cell. 2000 May;11(5):1585-95
references.pmid: 10793137
references.citation: J Virol. 2001 Dec;75(23):11583-93
references.pmid: 11689640
references.citation: J Virol. 2005 Apr;79(8):4557-67
references.pmid: 15795242
references.citation: N Engl J Med. 2005 Mar 31;352(13):1317-23
references.pmid: 15800227
references.citation: Nat Cell Biol. 2004 Jun;6(6):507-14
references.pmid: 15146192
references.citation: Cancer. 2004 Jul 15;101(2):317-24
references.pmid: 15241829
references.citation: Blood. 1995 Aug 15;86(4):1276-80
references.pmid: 7632932
references.citation: Transplant Rev (Orlando). 2008 Oct;22(4):252-61
references.pmid: 18656341
references.citation: N Engl J Med. 2007 Sep 27;357(13):1352-3
references.pmid: 17898112
references.citation: J Acquir Immune Defic Syndr. 2004 Jun 1;36(2):678-83
references.pmid: 15167286
references.citation: AIDS. 2000 Sep 29;14(14):2109-16
references.pmid: 11061651
references.citation: Nat Med. 2006 Aug;12(8):908-16
references.pmid: 16862153
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11318-22
references.pmid: 16844778
references.citation: J Virol. 2005 Aug;79(16):10740-9
references.pmid: 16051866
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000742
references.pmid: 20126446
references.citation: J Cell Sci. 2003 Sep 15;116(Pt 18):3721-8
references.pmid: 12890756
references.citation: Cancer Res. 2008 Oct 15;68(20):8361-8
references.pmid: 18922908
references.citation: AIDS. 2000 Sep 8;14(13):1907-10
references.pmid: 10997393
references.citation: J Virol. 2007 Apr;81(8):3949-68
references.pmid: 17287275
references.citation: Res Virol. 1996 Sep-Oct;147(5):267-75
references.pmid: 8880996
references.citation: Arch Dermatol Res. 1997 Jun;289(7):421-8
references.pmid: 9248622
references.citation: Blood. 1996 Jul 1;88(1):297-301
references.pmid: 8704186
references.citation: J Clin Invest. 2006 Jul;116(7):1963-73
references.pmid: 16794734
references.citation: Virology. 2001 Apr 10;282(2):245-55
references.pmid: 11289807
references.citation: Hematol Oncol Clin North Am. 2003 Jun;17(3):747-62
references.pmid: 12852654
references.citation: Science. 1988 Oct 21;242(4877):430-3
references.pmid: 2459779
references.citation: J Cutan Pathol. 2005 Jan;32(1):21-7
references.pmid: 15660651
references.citation: N Engl J Med. 1995 May 4;332(18):1186-91
references.pmid: 7700311
references.citation: Virology. 2008 Feb 5;371(1):139-54
references.pmid: 17964626
references.citation: Nat Rev Cancer. 2009 Jan;9(1):28-39
references.pmid: 19104514
references.citation: J Clin Invest. 2004 Jan;113(1):124-36
references.pmid: 14702116
references.citation: J Virol. 2005 Aug;79(16):10308-29
references.pmid: 16051824
references.citation: J Gen Virol. 2006 Apr;87(Pt 4):795-802
references.pmid: 16528027
references.citation: Cancer Sci. 2007 Oct;98(10):1536-9
references.pmid: 17645779
references.citation: Oncogene. 2008 Apr 10;27(17):2478-87
references.pmid: 17968312
references.citation: J Virol. 2007 Aug;81(16):8730-41
references.pmid: 17522206
references.citation: Blood. 2007 Mar 1;109(5):2165-73
references.pmid: 17082322
references.citation: Cancer Treat Rev. 2006 Oct;32(6):445-55
references.pmid: 16860939
references.citation: Cytokine Growth Factor Rev. 2007 Oct-Dec;18(5-6):395-402
references.pmid: 17656146
references.citation: N Engl J Med. 1999 Apr 8;340(14):1063-70
references.pmid: 10194235
references.citation: Int J Cancer. 2008 Jul 1;123(1):187-94
references.pmid: 18435450
references.citation: J Leukoc Biol. 2010 Jan;87(1):25-34
references.pmid: 20052801
references.citation: PLoS Pathog. 2007 Mar;3(3):e44
references.pmid: 17397260
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3456-61
references.pmid: 18519777
references.citation: Antimicrob Agents Chemother. 2004 Mar;48(3):867-72
references.pmid: 14982777
references.citation: J Pathol. 2006 Jan;208(2):187-98
references.pmid: 16362980