The transcriptional regulator NAB2 reveals a two-step induction of TRAIL in activated plasmacytoid DCs

Authors

  • Melania Balzarolo,

    1. Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
    2. Department of Hematopoiesis, Sanquin Research-AMC Landsteiner Laboratory, Amsterdam, the Netherlands
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  • Julien J. Karrich,

    1. Department of Cell Biology & Histology, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
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  • Sander Engels,

    1. Department of Hematopoiesis, Sanquin Research-AMC Landsteiner Laboratory, Amsterdam, the Netherlands
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  • Bianca Blom,

    1. Department of Cell Biology & Histology, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
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  • Jan Paul Medema,

    1. Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
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    • These authors shared senior authorship.

  • Monika C. Wolkers

    Corresponding author
    1. Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
    2. Department of Hematopoiesis, Sanquin Research-AMC Landsteiner Laboratory, Amsterdam, the Netherlands
    • Full correspondence: Dr. Monika C. Wolkers, Department of Hematopoiesis, Sanquin Research-AMC Landsteiner Laboratory, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands

      Fax: +31-20-5123474

      e-mail: m.wolkers@sanquin.nl

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    • These authors shared senior authorship.


Abstract

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.

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