Notch1 augments NF-κB activity by facilitating its nuclear retention

Mu Shin Hyun, Lisa M. Minter, Hyun Cho Ok, Sridevi Gottipati, Abdul H. Fauq, Todd E. Golde, Gail E. Sonenshein, Barbara A. Osborne

Research output: Contribution to journalArticlepeer-review

249 Scopus citations

Abstract

Notch1 specifically upregulates expression of the cytokine interferon-γ in peripheral T cells through activation of NF-κB. However, how Notch mediates NF-κB activation remains unclear. Here, we examined the temporal relationship between Notch signaling and NF-κB induction during T-cell activation. NF-κB activation occurs within minutes of T-cell receptor (TCR) engagement and this activation is sustained for at least 48 h following TCR signaling. We used γ-secretase inhibitor (GSI) to prevent the cleavage and subsequent activation of Notch family members. We demonstrate that GSI blocked the later, sustained NF-κB activation, but did not affect the initial activation of NF-κB. Using biochemical approaches, as well as confocal microscopy, we show that the intracellular domain of Notch1 (N1IC) directly interacts with NF-κB and competes with IκBα, leading to retention of NF-κB in the nucleus. Additionally, we show that N1IC can directly regulate IFN-γ expression through complexes formed on the IFN-γ promoter. Taken together, these data suggest that there are two 'waves' of NF-κB activation: an initial, Notch-independent phase, and a later, sustained activation of NF-κB, which is Notch dependent.

Original languageEnglish
Pages (from-to)129-138
Number of pages10
JournalEMBO Journal
Volume25
Issue number1
DOIs
StatePublished - 11 Jan 2006
Externally publishedYes

Keywords

  • Interferon-γ
  • IκBα
  • NF-κB
  • Notch1

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