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Notch1 augments NF-kappaB activity by facilitating its nuclear retention

Hyun Mu Shin1, Lisa M Minter, Ok Hyun Cho

  • 1Molecular and Cellular Biology Program, University of Massachusetts/Amherst, Amherst, MA 01003, USA.

The EMBO Journal
|December 2, 2005
PubMed

Insights

Notch1 signaling influences T-cell activation by regulating NF-kappaB. This study reveals a two-phase NF-kappaB activation process, with a later phase dependent on Notch1 for sustained interferon-gamma expression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Notch1 signaling is known to upregulate interferon-gamma (IFN-gamma) in T cells via NF-kappaB activation.
  • The precise mechanism by which Notch mediates NF-kappaB activation during T-cell activation remains incompletely understood.

Purpose of the Study:

  • To investigate the temporal dynamics of Notch signaling and NF-kappaB induction during T-cell activation.
  • To elucidate the role of Notch1 in mediating sustained NF-kappaB activation and subsequent IFN-gamma expression.

Main Methods:

  • Utilized gamma-secretase inhibitor (GSI) to block Notch activation.
  • Employed biochemical assays and confocal microscopy to study protein interactions.
  • Examined the temporal relationship between T-cell receptor (TCR) engagement and NF-kappaB activation.

Main Results:

  • NF-kappaB activation occurs in two phases: an initial rapid phase and a later sustained phase.
  • GSI treatment inhibited the sustained NF-kappaB activation but not the initial phase.
  • The intracellular domain of Notch1 (N1IC) directly interacts with NF-kappaB, promoting its nuclear retention and regulating IFN-gamma expression.

Conclusions:

  • T-cell activation involves a dual-phase NF-kappaB activation pathway.
  • The sustained phase of NF-kappaB activation and subsequent IFN-gamma upregulation are dependent on Notch1 signaling.
  • Notch1 plays a critical role in regulating the late, sustained immune response mediated by T cells.

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