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Sci. Signal., 3 August 2010
Vol. 3, Issue 133, p. ra59
[DOI: 10.1126/scisignal.2000976]

RESEARCH ARTICLES

The Nonphagocytic NADPH Oxidase Duox1 Mediates a Positive Feedback Loop During T Cell Receptor Signaling

Jaeyul Kwon1,2*, Kristen E. Shatynski1, Haiyan Chen1, Stanislas Morand2, Xavier de Deken3, Françoise Miot3, Thomas L. Leto2, and Mark S. Williams1*

1 Center for Vascular and Inflammatory Diseases, Department of Microbiology and Immunology, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD 21201, USA.
2 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852, USA.
3 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Campus Erasme, 1070 Brussels, Belgium.

Abstract: Production of reactive oxygen species, often by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, plays a role in the signaling responses of cells to many receptor stimuli. Here, we describe the function of the calcium-dependent, nonphagocytic NADPH oxidase Duox1 in primary human CD4+ T cells and cultured T cell lines. Duox1 bound to inositol 1,4,5-trisphosphate receptor 1 and was required for early T cell receptor (TCR)–stimulated production of hydrogen peroxide (H2O2) through a pathway that was dependent on TCR-proximal kinases. Transient or stable knockdown of Duox1 inhibited TCR signaling, especially phosphorylation of tyrosine-319 of {zeta} chain–associated protein kinase of 70 kilodaltons (ZAP-70), store-operated entry of calcium ions (Ca2+), and activation of extracellular signal–regulated kinase. The production of cytokines was also inhibited by knockdown of Duox1. Duox1-mediated inactivation of Src homology 2 domain–containing protein tyrosine phosphatase 2 promoted the phosphorylation of ZAP-70 and its association with the Src family tyrosine kinase Lck and the CD3{zeta} chain of the TCR complex. Thus, we suggest that activation of Duox1, downstream of proximal TCR signals, generates H2O2 that acts in a positive feedback loop to enhance and sustain further TCR signaling.

* To whom correspondence should be addressed. E-mail: marwilliams{at}som.umaryland.edu (M.S.W.); kwonja{at}niaid.nih.gov (J.K.)

Citation: J. Kwon, K. E. Shatynski, H. Chen, S. Morand, X. de Deken, F. Miot, T. L. Leto, M. S. Williams, The Nonphagocytic NADPH Oxidase Duox1 Mediates a Positive Feedback Loop During T Cell Receptor Signaling. Sci. Signal. 3, ra59 (2010).

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