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T-cell receptor-induced NF-kappaB activation is negatively regulated by E3 ubiquitin ligase Cbl-b

Guilin Qiao1, Zhenping Li, Luciana Molinero

  • 1Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 5100, Suite S-521, Chicago, IL 60637, USA.

Molecular and Cellular Biology
|January 30, 2008
PubMed

Insights

The E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) normally inhibits T-cell activation. Its absence leads to abnormal NF-kappaB activation via Akt and protein kinase C-theta (PKC-theta) signaling pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) is known to inhibit T-cell activation.
  • The precise molecular mechanisms of Cbl-b-mediated inhibition remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Cbl-b regulates T-cell activation.
  • To investigate the role of Cbl-b in NF-kappaB activation following T-cell receptor (TCR) ligation.

Main Methods:

  • Analysis of NF-kappaB activation in T cells lacking Cbl-b.
  • Investigating the involvement of phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C-theta (PKC-theta) signaling pathways.
  • Studying the formation of the CARMA1-Bcl10-MALT1 (CBM) complex.

Main Results:

  • Loss of Cbl-b leads to aberrant NF-kappaB activation upon TCR ligation.
  • This aberrant activation is mediated by both PI3-K/Akt and PKC-theta signaling.
  • Cbl-b associates with and regulates PKC-theta activation via Vav-1, influencing the IKK complex and NF-kappaB activation.

Conclusions:

  • Cbl-b negatively regulates T-cell activation by controlling NF-kappaB signaling.
  • Down-regulation of TCR-induced NF-kappaB activation by Cbl-b involves both Akt-dependent and PKC-theta-dependent pathways.
  • These findings provide novel insights into the molecular regulation of T-cell activation by Cbl-b.

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