Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Cell Transformation, Viral*; Cytomegalovirus/*metabolism ; Herpesvirus 8, Human/*metabolism ; NFATC Transcription Factors/*metabolism ; Receptors, Chemokine/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism ; Viral Proteins/*metabolism; Animals ; Cytomegalovirus/genetics ; HEK293 Cells ; Herpesvirus 8, Human/genetics ; Humans ; Mice ; NFATC Transcription Factors/genetics ; Receptors, Chemokine/genetics ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics ; Viral Proteins/genetics

G protein-coupled receptors (GPCRs) constitute the largest family of proteins that transmit signal to regulate an array of fundamental biological processes. Viruses deploy diverse tactics to hijack and harness intracellular signaling events induced by GPCR. Herpesviruses encode multiple GPCR homologues that are implicated in viral pathogenesis. Cellular GPCRs are primarily regulated by their cognate ligands, while herpesviral GPCRs constitutively activate downstream signaling cascades, including the nuclear factor of activated T cells (NFAT) pathway. However, the roles of NFAT activation and mechanism thereof in viral GPCR tumorigenesis remain unknown. Here we report that GPCRs of human Kaposi's sarcoma-associated herpesvirus (kGPCR) and cytomegalovirus (US28) shortcut NFAT activation by inhibiting the sarcoplasmic reticulum calcium ATPase (SERCA), which is necessary for viral GPCR tumorigenesis. Biochemical approaches, entailing pharmacological inhibitors and protein purification, demonstrate that viral GPCRs target SERCA2 to increase cytosolic calcium concentration. As such, NFAT activation induced by vGPCRs was exceedingly sensitive to cyclosporine A that targets calcineurin, but resistant to inhibition upstream of ER calcium release. Gene expression profiling identified a signature of NFAT activation in endothelial cells expressing viral GPCRs. The expression of NFAT-dependent genes was up-regulated in tumors derived from tva-kGPCR mouse and human KS. Employing recombinant kGPCR-deficient KSHV, we showed that kGPCR was critical for NFAT-dependent gene expression in KSHV lytic replication. Finally, cyclosporine A treatment diminished NFAT-dependent gene expression and tumor formation induced by viral GPCRs. These findings reveal essential roles of NFAT activation in viral GPCR tumorigenesis and a mechanism of "constitutive" NFAT activation by viral GPCRs.

Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2538-42. (PMID: 10051678)
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7214-9. (PMID: 10377394)
Biochim Biophys Acta. 1999 Jul 8;1450(3):191-231. (PMID: 10395934)
J Biol Chem. 2000 Aug 4;275(31):23627-35. (PMID: 10816557)
Mol Cell. 2000 Sep;6(3):539-50. (PMID: 11030334)
J Biol Chem. 2001 Jan 12;276(2):1376-82. (PMID: 11031271)
J Biol Chem. 2001 Jan 12;276(2):1133-7. (PMID: 11050102)
Cancer Res. 2001 Feb 15;61(4):1255-9. (PMID: 11245414)
J Biol Chem. 2001 May 25;276(21):18563-9. (PMID: 11278747)
Cancer Res. 2001 Mar 1;61(5):2145-53. (PMID: 11280779)
Inflamm Res. 2001 Apr;50(4):220-6. (PMID: 11392610)
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3932-7. (PMID: 11867761)
Nat Cell Biol. 2002 Jul;4(7):540-4. (PMID: 12080349)
Mol Cell. 2002 Nov;10(5):1071-81. (PMID: 12453415)
J Virol. 2003 Jan;77(1):57-67. (PMID: 12477810)
Cancer Cell. 2003 Jan;3(1):23-36. (PMID: 12559173)
Nucleic Acids Res. 2003 Feb 1;31(3):911-21. (PMID: 12560487)
J Virol. 2003 May;77(10):5759-73. (PMID: 12719569)
Genes Dev. 2003 Sep 15;17(18):2205-32. (PMID: 12975316)
Nat Genet. 1992 Sep;2(1):31-6. (PMID: 1303245)
Thromb Haemost. 2003 Oct;90(4):570-6. (PMID: 14515175)
Clin Cancer Res. 2004 Feb 1;10(3):803-21. (PMID: 14871955)
Semin Oncol. 2004 Apr;31(2 Suppl 7):2-11. (PMID: 15179620)
Cancer Cell. 2004 Nov;6(5):507-16. (PMID: 15542434)
Nat Rev Mol Cell Biol. 2004 Dec;5(12):998-1012. (PMID: 15573137)
Trends Pharmacol Sci. 2005 Aug;26(8):405-11. (PMID: 15990176)
Blood. 2005 Nov 15;106(10):3546-52. (PMID: 16051745)
Trends Pharmacol Sci. 2006 Jan;27(1):56-63. (PMID: 16352349)
J Biol Chem. 2006 May 5;281(18):12210-7. (PMID: 16505480)
Nature. 2006 Jun 1;441(7093):646-50. (PMID: 16511445)
Nature. 2006 Jun 1;441(7093):595-600. (PMID: 16554754)
Cancer Cell. 2006 Aug;10(2):133-43. (PMID: 16904612)
J Virol. 2007 Jan;81(1):42-58. (PMID: 17050609)
Nat Rev Cancer. 2007 Feb;7(2):79-94. (PMID: 17251915)
Cell Cycle. 2007 Jul 15;6(14):1789-95. (PMID: 17637565)
Cancer Cell. 2008 May;13(5):420-31. (PMID: 18455125)
FASEB J. 2008 Dec;22(12):4218-27. (PMID: 18708588)
PLoS Pathog. 2008 Sep 19;4(9):e1000157. (PMID: 18802460)
J Lipid Res. 2009 Apr;50 Suppl:S237-42. (PMID: 19011112)
Carcinogenesis. 2009 Mar;30(3):377-86. (PMID: 19136477)
Cancer Res. 2009 Apr 1;69(7):2861-9. (PMID: 19318580)
Biochim Biophys Acta. 2009 Jul;1793(7):1315-24. (PMID: 19348862)
Nature. 2009 Jun 25;459(7250):1126-30. (PMID: 19458618)
BMC Med Genomics. 2009 Aug 06;2:50. (PMID: 19660139)
Nat Rev Cancer. 2009 Nov;9(11):810-20. (PMID: 19851316)
J Virol. 2010 Apr;84(7):3351-61. (PMID: 20106924)
PLoS Pathog. 2010 Feb 12;6(2):e1000777. (PMID: 20169190)
Mol Cell Endocrinol. 2011 Jan 15;331(2):179-84. (PMID: 20398729)
Clin Cancer Res. 2010 Jun 1;16(11):2927-31. (PMID: 20484021)
Expert Rev Proteomics. 2010 Jun;7(3):401-9. (PMID: 20536310)
PLoS One. 2010 Jul 06;5(7):e11435. (PMID: 20625401)
PLoS Pathog. 2010 Jul 29;6(7):e1001001. (PMID: 20686657)
Nat Rev Immunol. 2010 Sep;10(9):645-56. (PMID: 20725108)
Nat Rev Cancer. 2010 Oct;10(10):707-19. (PMID: 20865011)
J Virol. 2010 Dec;84(24):12733-53. (PMID: 20943963)
Cancer Cell. 2011 Jun 14;19(6):805-13. (PMID: 21665152)
PLoS One. 2011;6(9):e24379. (PMID: 21980345)
PLoS Pathog. 2011 Nov;7(11):e1002336. (PMID: 22110409)
Circ Res. 2012 Jun 8;110(12):1646-60. (PMID: 22679139)
J Virol. 2012 Sep;86(18):9708-20. (PMID: 22740391)
J Biol Chem. 2012 Oct 19;287(43):36593-608. (PMID: 22927430)
PLoS Pathog. 2012 Sep;8(9):e1002927. (PMID: 23028325)
Annu Rev Pharmacol Toxicol. 2013;53:331-54. (PMID: 23092247)
Annu Rev Pharmacol Toxicol. 2013;53:531-56. (PMID: 23140243)
Oncogenesis. 2012 Apr 02;1:e5. (PMID: 23552603)
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11139-44. (PMID: 23771900)
Cell Rep. 2013 Aug 29;4(4):709-23. (PMID: 23954784)
Nat Rev Drug Discov. 2014 Feb;13(2):123-39. (PMID: 24445563)
Cell Host Microbe. 2014 Mar 12;15(3):266-82. (PMID: 24629334)
J Virol. 2014 Dec;88(23):13858-78. (PMID: 25253349)
PLoS Pathog. 2014 Oct 23;10(10):e1004460. (PMID: 25340789)
N Engl J Med. 1995 May 4;332(18):1186-91. (PMID: 7700311)
Science. 1994 Dec 16;266(5192):1865-9. (PMID: 7997879)
Nature. 1997 Jan 23;385(6614):347-50. (PMID: 9002520)
Science. 1997 Mar 28;275(5308):1930-4. (PMID: 9072970)
Science. 1997 Jul 4;277(5322):55-60. (PMID: 9204896)
Cell. 1998 May 29;93(5):851-61. (PMID: 9630228)

CA134241 United States CA NCI NIH HHS; DE021445 United States DE NIDCR NIH HHS; R01 DE021445 United States DE NIDCR NIH HHS; R01 CA134241 United States CA NCI NIH HHS; CA180779 United States CA NCI NIH HHS; R01 DE023926 United States DE NIDCR NIH HHS; P01 CA180779 United States CA NCI NIH HHS

0 (NFATC Transcription Factors)
0 (Receptors, Chemokine)
0 (US28 receptor, Cytomegalovirus)
0 (Viral Proteins)
EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)

Date Created: 20150327 Date Completed: 20160208 Latest Revision: 20201217

20240829

PMC4374719

10.1371/journal.ppat.1004768

25811856