Polyomavirus JC (JCV) infects oligodendrocytes and astrocytes in the brain and is the cause of the demyelinating disease progressive multifocal leukoencephalopathy (PML). In cell culture, JCV infection is characterized by severe damage to cellular DNA, which begins early in infection, and a viral cytopathic effect, which is observed late in infection. Nevertheless, these JCV-infected cells show a low level of apoptosis, at both the early and late stages of infection. This suggests that there is conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g. through T antigen (T-Ag)–p53 interaction, and cellular pro-apoptotic pathways that seek to eliminate virally infected cells. The apoptosis regulatory protein BAG3 is a member of the human Bcl-2-associated athanogene (BAG) family of proteins, which function as molecular co-chaperones through their interaction with Hsc70/Hsp70 and function in the regulation of the cellular stress response, proliferation and apoptosis. This study showed that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV T-Ag via repression of the BAG3 promoter. The site of action of T-Ag was mapped to an AP2 site in the BAG3 promoter, and gel shift and chromatin immunoprecipitation assays showed that T-Ag inhibited AP2 binding to this site, resulting in downregulation of BAG3 promoter expression. Using BAG3 and T-Ag expression and BAG3 siRNA, it was found that BAG3 and T-Ag had antagonistic effects on the induction of apoptosis, being anti-apoptotic and pro-apoptotic, respectively. The significance of these interactions to the JCV life cycle is discussed.
AminiS.,
MameliG.,
Del ValleL.,
SkowronskaA.,
ReissK.,
GelmanB. B.,
WhiteM. K.,
KhaliliK.,
SawayaB. E.2005; p73 interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. Mol Cell Biol 25:8126–8138[CrossRef]
BriveL.,
TakayamaS.,
BriknarováK.,
HommaS.,
IshidaS. K.,
ReedJ. C.,
ElyK. R.2001; The carboxyl-terminal lobe of Hsc70 ATPase domain is sufficient for binding to BAG1. Biochem Biophys Res Commun 289:1099–1105[CrossRef]
ColeC. N.1996; Polyomavirinae : the viruses and their replication. In Fundamental Virology , 3rd edn. pp 917–946Edited byFieldsB. N.,
KnipeD. M.,
HowleyP. M.
Philadelphia: Lippincott, Williams & Wilkins;
Darbinian-SarkissianN.,
CzernikM.,
PeruzziF.,
GordonJ.,
RappaportJ.,
ReissK.,
KhaliliK.,
AminiS.2006; Dysregulation of NGF-signaling and Egr-1 expression by Tat in neuronal cell culture. J Cell Physiol 208:506–515[CrossRef]
DarbinyanA.,
WhiteM. K.,
AkanS.,
RadhakrishnanS.,
Del ValleL.,
AminiS.,
KhaliliK.2007; Alterations of DNA damage repair pathways resulting from JCV infection. Virology 364:73–86[CrossRef]
Del ValleL.,
GordonJ.,
EnamS.,
DelbueS.,
CroulS.,
AbrahamS.,
RadhakrishnanS.,
AssimakopoulouM.,
KatsetosC. D.,
KhaliliK.2002; Expression of human neurotropic polyomavirus JCV late gene product agnoprotein in human medulloblastoma. J Natl Cancer Inst 94:267–273[CrossRef]
Del ValleL.,
WhiteM. K.,
KhaliliK.2008; Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:729–740[CrossRef]
DevireddyL. R.,
KumarK. U.,
PaterM. M.,
PaterA.2000; BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus. J Gen Virol 81:351–357
DoongH.,
PriceJ.,
KimY. S.,
GasbarreC.,
ProbstJ.,
LiottaL. A.,
BlanchetteJ.,
RizzoK.,
KohnE.2000; CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C- γ and Hsp70/Hsc70. Oncogene 19:4385–4395[CrossRef]
FrisqueR. J.,
WhiteF. A.1992; The molecular biology of JC virus, causative agent of progressive multifocal leukoencephalopathy. In Molecular Neurovirology pp 25–160Edited byRoosR. P.
Totawa, NJ: Humana Press;
GentilellaA.,
PassiatoreG.,
DeshmaneS.,
TurcoM. C.,
KhaliliK.2008; Activation of BAG3 by Egr-1 in response to FGF-2 in neuroblastoma cells. Oncogene 27:5011–5018[CrossRef]
KassisJ. N.,
GuancialE. A.,
DoongH.,
ViradorV.,
KohnE. C.2006; CAIR-1/BAG-3 modulates cell adhesion and migration by downregulating activity of focal adhesion proteins. Exp Cell Res 312:2962–2971[CrossRef]
KelleyW. L.,
GeorgopoulosC.1997; The T/t common exon of simian virus 40, JC, and BK polyomavirus T antigens can functionally replace the J-domain of the Escherichia coli DnaJ molecular chaperone. Proc Natl Acad Sci U S A 94:3679–3684[CrossRef]
KrynskaB.,
GordonJ.,
OtteJ.,
FranksR.,
KnoblerR.,
DeLucaA.,
GiordanoA.,
KhaliliK.1997; Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein. J Cell Biochem 67:223–230[CrossRef]
LassakA.,
Del ValleL.,
PeruzziF.,
WangJ. Y.,
EnamS.,
CroulS.,
KhaliliK.,
ReissK.2002; Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen. J Biol Chem 277:17231–17238[CrossRef]
LeeJ. H.,
TakahashiT.,
YasuharaN.,
InazawaJ.,
KamadaS.,
TsujimotoY.1999; Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death. Oncogene 18:6183–6190[CrossRef]
LinzerD. I.,
LevineA. J.1979; Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52[CrossRef]
MázlóM.,
RessetarH. G.,
StonerG. L.2001; The neuropathology and pathogenesis of progressive multifocal leukoencephalopathy. In Human Polyomaviruses: Molecular and Clinical Perspectives pp 257–335Edited byKhaliliK.,
StonerG. L.
New York: Wiley;
McPhersonL. A.,
WeigelR. J.1999; AP2 α and AP2 γ : a comparison of binding site specificity and trans-activation of the estrogen receptor promoter and single site promoter constructs. Nucleic Acids Res 27:4040–4049[CrossRef]
MitchellP. J.,
WangC.,
TjianR.1987; Positive and negative regulation of transcription in vitro : enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell 50:847–861[CrossRef]
PagliucaM. G.,
LeroseR.,
CiglianoS.,
LeoneA.2003; Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity. FEBS Lett 541:11–15[CrossRef]
Piña-OviedoS.,
UrbanskaK.,
RadhakrishnanS.,
SweetT.,
ReissK.,
KhaliliK.,
Del ValleL.2007; Effects of JC virus infection on anti-apoptotic protein survivin in progressive multifocal leukoencephalopathy. Am J Pathol 170:1291–1304[CrossRef]
RadhakrishnanS.,
GordonJ.,
Del ValleL.,
CuiJ.,
KhaliliK.2004; Intracellular approach for blocking JC virus gene expression by using RNA interference during viral infection. J Virol 78:7264–7269[CrossRef]
RomagnoliL.,
SariyerI. K.,
TungJ.,
FelicianoM.,
SawayaB. E.,
Del ValleL.,
FerranteP.,
KhaliliK.,
SafakM.,
WhiteM. K.2008; Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:331–341[CrossRef]
RosatiA.,
AmmiranteM.,
GentilellaA.,
BasileA.,
FestaM.,
PascaleM.,
MarzulloL.,
BelisarioM. A.,
ToscoA. & other authors (2007a). Apoptosis inhibition in cancer cells: a novel molecular pathway that involves BAG3 protein. Int J Biochem Cell Biol 39:1337–1342[CrossRef]
SawaiE. T.,
ButelJ. S.1989; Association of a cellular heat shock protein with simian virus 40 large T antigen in transformed cells. J Virol 63:3961–3973
SethP.,
DiazF.,
Tao-ChengJ. H.,
MajorE. O.2004; JC virus induces nonapoptotic cell death of human central nervous system progenitor cell-derived astrocytes. J Virol 78:4884–4891[CrossRef]
SomasundaramK.,
JayaramanG.,
WilliamsT.,
MoranE.,
FrischS.,
ThimmapayaB.1996; Repression of a matrix metalloprotease gene by E1A correlates with its ability to bind to cell type-specific transcription factor AP-2. Proc Natl Acad Sci U S A 93:3088–3093[CrossRef]
TakayamaS.,
SatoT.,
KrajewskiS.,
KochelK.,
IrieS.,
MillanJ. A.,
ReedJ. C.1995; Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 80:279–284[CrossRef]
WhiteM. K.,
AminiS.,
KhaliliK.,
DarbinianN.2008; Development of a bidirectional caspase-3 expression system for the induction of apoptosis. Cancer Biol Ther 7:945–954[CrossRef]