Sci Signal
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.
Published: August 2010
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 (H(2)O(2)) 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 (Ca(2+)), 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 CD3zeta chain of the TCR complex. Thus, we suggest that activation of Duox1, downstream of proximal TCR signals, generates H(2)O(2) that acts in a positive feedback loop to enhance and sustain further TCR signaling.
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http://dx.doi.org/10.1126/scisignal.2000976 | DOI Listing |
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Norwich Medical School, University of East Anglia, Norwich, UK.
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Department of Biochemistry, Kawasaki Medical School, 577 Matsushima Kurashiki, Okayama, 701-0192, Japan.
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Fondazione Istituto di Ricerca Pediatrica Città della Speranza - IRP, Padova, Italy.
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Department of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.
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