Human parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells.
The pathogenic mechanism by which parvovirus B19 may induce inflammatory cardiomyopathy (iCMP) is complex but is known to involve inflammatory processes, possibly including activation of JAK/STAT signaling. The nonstructural B19 protein NS1 acts as a transactivator triggering signaling cascades that eventually lead to activation of interleukin 6 (IL-6). We examined the impact of NS1 on modulation of STAT signaling in human endothelial cells (HMEC-1). The NS1 sequences were identified from B19 DNA isolated from the myocardia of patients with fatal iCMP. B19 infection as well as NS1 overexpression in HMEC-1 cells produced a significant upregulation in the phosphorylation of both tyrosine(705) and serine(727) STAT3 (P < 0.05). The increased STAT3 phosphorylation was accompanied by dimerization, nuclear translocation, and DNA binding of pSTAT3. In contrast, NS1 expression did not result in increased STAT1 activation. Notably, the expression levels of the negative regulators of STAT activation, SOCS1 and SOCS3, were not altered by NS1. However, the level of PIAS3 was upregulated in NS1-expressing HMEC-1 cells. Analysis of the transcriptional activation of target genes revealed that NS1-induced STAT3 signaling was associated with upregulation of genes involved in immune response (e.g., the IFNAR1 and IL-2 genes) and downregulation of genes associated with viral defense (e.g., the OAS1 and TYK2 genes). Our results demonstrate that B19 NS1 modulates the STAT/PIAS pathway. The NS1-induced upregulation of STAT3/PIAS3 in the absence of STAT1 phosphorylation and the lack of SOCS1/SOCS3 activation may contribute to the mechanisms by which B19 evades the immune response and establishes persistent infection in human endothelial cells. Thus, NS1 may play a critical role in the mechanism of viral pathogenesis in B19-associated iCMP.
Department of Molecular Pathology, Institute for Pathology, University of Tuebingen, 72076 Tuebingen, Germany.
Anja
A
Duechting
Carsten
C
Tschöpe
Heike
H
Kaiser
Tobias
T
Lamkemeyer
Nobuyuki
N
Tanaka
Susanne
S
Aberle
Florian
F
Lang
Joseph
J
Torresi
Reinhard
R
Kandolf
C-Thomas
CT
Bock
D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019281:Dimerization; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007249:Inflammation; D018832:Molecular Chaperones / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D016732:Parvovirus B19, Human / Q000378:metabolism*; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000737:chemistry*; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000737:chemistry*
D018832:Molecular Chaperones; C106202:NS1 protein, parvovirus; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017361:Viral Nonstructural Proteins