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Striking back at the activator: how IkappaB kinase terminates antigen receptor responses

Michael Hinz1, Claus Scheidereit

  • 1Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.

Science'S STKE : Signal Transduction Knowledge Environment
|May 3, 2007
PubMed

Insights

TCR signaling activates NF-kappaB via IKK. IKKbeta phosphorylates Bcl10, disrupting the CBM complex to terminate signaling and prevent immune dysregulation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • T cell receptor (TCR) signaling activates Nuclear Factor kappa B (NF-kappaB) through IkappaB kinases (IKK).
  • NF-kappaB controls lymphocyte functions, necessitating precise temporal regulation of its activation.
  • Mechanisms for terminating TCR-induced signaling remain less understood compared to activation pathways.

Purpose of the Study:

  • To investigate the negative feedback mechanisms regulating TCR-induced NF-kappaB pathway termination.
  • To elucidate the role of the scaffold protein Bcl10 in signaling termination.

Main Methods:

  • Investigated the interaction between IKK and the CBM complex components (CARMA1, Bcl10, Malt1).
  • Analyzed the phosphorylation status of Bcl10 by IKKbeta.
  • Examined the effect of Bcl10 phosphorylation on CBM complex stability and NF-kappaB activation.

Main Results:

  • Bcl10 serves as a negative feedback substrate for IKK.
  • IKKbeta initially promotes CBM complex formation for activation, then phosphorylates Bcl10 to disrupt the complex and terminate signaling.
  • IKK-mediated Bcl10 phosphorylation also targets it for degradation via the ubiquitin-proteasome system.

Conclusions:

  • Negative feedback mechanisms are intrinsic to the termination of TCR-induced NF-kappaB signaling.
  • The scaffold protein Bcl10 plays a critical role in both initiating and terminating TCR signaling through IKK-mediated phosphorylation.

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