Multiple Levels of Control Determine How E4bp4/Nfil3 Regulates NK Cell Development

The transcription factor E4bp4/Nfil3 has been shown to have a critical role in the development of all innate lymphoid cell types including NK cells. In this study, we show that posttranslational modifications of E4bp4 by either SUMOylation or phosphorylation have profound effects on both E4bp4 funct...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2018-02, Vol.200 (4), p.1370-1381
Main Authors: Kostrzewski, Tomasz, Borg, Aaron J, Meng, Yiran, Filipovic, Iva, Male, Victoria, Wack, Andreas, DiMaggio, Peter A, Brady, Hugh J M
Format: Article
Language:English
Subjects:
Animals
Basic-Leucine Zipper Transcription Factors - immunology
Basic-Leucine Zipper Transcription Factors - metabolism
Cell Differentiation - immunology
Cell Lineage - immunology
Gene Expression Regulation - immunology
HEK293 Cells
HeLa Cells
Humans
Killer Cells, Natural - cytology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutants
Natural killer cells
Notch1 protein
Phosphorylation
Protein Processing, Post-Translational
Receptor, Notch1 - biosynthesis
Receptor, Notch1 - immunology
SUMO protein
T cell receptors
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Summary:The transcription factor E4bp4/Nfil3 has been shown to have a critical role in the development of all innate lymphoid cell types including NK cells. In this study, we show that posttranslational modifications of E4bp4 by either SUMOylation or phosphorylation have profound effects on both E4bp4 function and NK cell development. We examined the activity of E4bp4 mutants lacking posttranslational modifications and found that was a novel E4bp4 target gene. We observed that abrogation of Notch signaling impeded NK cell production and the total lack of NK cell development from progenitors was completely rescued by short exposure to Notch peptide ligands. This work reveals both novel mechanisms in NK cell development by a transcriptional network including E4bp4 with Notch, and that E4bp4 is a central hub to process extrinsic stimuli.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1700981