Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes.

Molecular Immunology
Amde Selassie Shifera, Marshall S Horwitz

Abstract

Mutations in the zinc finger of I kappa B kinase gamma (IKK gamma) are associated with hypohidrotic ectodermal dysplasia-immune deficiency (HED-ID) in which the major immune deficit is the inability to switch Ab heavy chain class. However, the pathophysiologic role of the mutations has not been fully delineated. Since help from activated Th cells is essential in Ab class switching, we sought to examine how these mutations affect T cell activation. Using a human T cell line that was null for IKK gamma, we generated cells stably expressing two of the reported mutations, namely, D406V and C417R. Cells expressing either mutation failed to induce IL-2 following stimulation with PMA/ionomycin while the induction of IL-2 was restored in cells reconstituted with the wild type IKK gamma. The lack of IL-2 upregulation correlated with the lack of NF-kappaB activation as evidenced by the inability to induce I kappa B alpha degradation, NF-kappaB binding to DNA and the expression of a reporter gene. However, both mutations did not prevent the incorporation of IKK gamma into the IKK complex and, interestingly, the induced phosphorylation of I kappa B alpha at S32 and S36 and its subsequent ubiquitination were not affected. The suppression of...Continue Reading

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Citations

Nov 20, 2010·Journal of Translational Medicine·Erica JohnMichael T Lotze
Mar 30, 2010·Journal of Cellular and Molecular Medicine·Amde Selassie Shifera
Jun 2, 2015·Biological & Pharmaceutical Bulletin·Hongkui ZhangLonglu Zhang
Sep 23, 2020·Signal Transduction and Targeted Therapy·Hui YuHongbo Hu
Apr 14, 2010·Immunology Letters·Amde Selassie ShiferaJohn A Hardin

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