The transcriptional regulator NAB2 reveals a two-step induction of TRAIL in activated plasmacytoid DCs.
Plasmacytoid dendritic cells (pDCs) are key players in antiviral immunity. In addition to massive type I interferon production, activated pDCs express the apoptosis-inducing molecule TRAIL, which enables them to clear infected cells that express the TRAIL receptors TRAIL-R1 and TRAIL-R2. In this study, we examined the molecular mechanisms that govern TRAIL expression in human pDCs. We identify NGFI-A-binding protein 2 (NAB2) as a novel transcriptional regulator that governs TRAIL induction in stimulated pDCs. We show with the pDC-like cell line CAL-1 that NAB2 is exclusively induced downstream of TLR7 and TLR9 signaling, and not upon type I IFN-R signaling. Furthermore, PI3K signaling is required for NAB2-mediated TRAIL expression. Finally, we show that TRAIL induction in CpG-activated human pDCs occurs through two independent signaling pathways: the first is initiated through TLR9 signaling upon recognition of nucleic acids, followed by type I IFN-R-mediated signaling. In conclusion, our data suggest that these two pathways are downstream of different activation signals, but act in concert to allow for full TRAIL expression in pDCs.
Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Melania
M
Balzarolo
Julien J
JJ
Karrich
Sander
S
Engels
Bianca
B
Blom
Jan Paul
JP
Medema
Monika C
MC
Wolkers
D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D058539:Phosphatidylinositol 3-Kinase / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
C491000:NAB2 protein, human; D012097:Repressor Proteins; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D012313:RNA; D016899:Interferon-beta; D058539:Phosphatidylinositol 3-Kinase