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Mol. Cell. Biol. 22 (2): 400-411

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Effect of Redox Balance Alterations on Cellular Localization of LAT and Downstream T-Cell Receptor Signaling Pathways

Sonja I. Gringhuis,* Ellen A. M. Papendrecht-van der Voort, Angela Leow, E. W. Nivine Levarht, Ferdinand C. Breedveld, and Cornelis L. Verweij,{dagger}

Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Received for publication 23 May 2001. Revision received 2 July 2001. Accepted for publication 9 October 2001.

Abstract: The integral membrane protein linker for activation of T cells (LAT) is a central adapter protein in the T-cell receptor (TCR)-mediated signaling pathways. The cellular localization of LAT is extremely sensitive to intracellular redox balance alterations. Reduced intracellular levels of the antioxidant glutathione (GSH), a hallmark of chronic oxidative stress, resulted in the membrane displacement of LAT, abrogated TCR-mediated signaling and consequently hyporesponsiveness of T lymphocytes. The membrane displacement of LAT is accompanied by a considerable difference in the mobility of LAT upon native and nonreducing denaturing polyacrylamide gel electrophoresis analysis, a finding indicative of a conformational change. Targeted mutation of redox-sensitive cysteine residues within LAT created LAT mutants which remain membrane anchored under conditions of chronic oxidative stress. The expression of redox-insensitive LAT mutants allows for restoration of TCR-mediated signal transduction, whereas CD28-mediated signaling pathways remained impaired. These results are indicative that the membrane displacement of LAT as a result of redox balance alterations is a consequence of a conformational change interfering with the insertion of LAT into the plasma membrane. Conclusively, the data suggest a role for LAT as a crucial intermediate in the sensitivity of TCR signaling and hence T lymphocytes toward chronic oxidative stress.

* Corresponding author. Mailing address: Department of Rheumatology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-526-4664. Fax: 31-71-526-6752. E-mail: s.i.gringhuis{at}lumc.nl.

{dagger} Present address: Department of Molecular Cell Biology, VU Medical Center, 1081 BT Amsterdam, The Netherlands.

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