Induction of the NF-kappaB Cascade by Recruitment of the Scaffold Molecule NEMO to the T Cell Receptor

Immunity. 2003 Jan;18(1):13-26. doi: 10.1016/s1074-7613(02)00506-x.

Abstract

The mechanism by which TCR signaling activates NF-kappaB is poorly understood. We demonstrate here that the IKK kinase complex is recruited to the immunological synapse and can be coprecipitated with the TCR after T cell activation. Using ZAP-70-deficient T cells expressing a hybrid molecule between the SH2 domain of ZAP-70 and NEMO/IKKgamma, we showed that targeting NEMO to the immunological synapse, and more specifically its 120 N-terminal amino acids, was sufficient to selectively restore NF-kappaB activation in response to TCR ligation. Finally, we demonstrated that targeting of NEMO to the membrane of T cells was sufficient to induce constitutive NF-kappaB activation. This study shows that the localization of NEMO to the immunological synapse is important for TCR-induced NF-kappaB activation and offers a powerful system to dissect the NF-kappaB cascade in T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD28 Antigens / metabolism
  • CD3 Complex / metabolism
  • Humans
  • I-kappa B Kinase
  • Jurkat Cells
  • Lymphocyte Activation
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Deletion
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • ZAP-70 Protein-Tyrosine Kinase
  • src Homology Domains

Substances

  • Antibodies, Monoclonal
  • CD28 Antigens
  • CD3 Complex
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human