Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase

Martina Ulrich, Alina Petre, Nikolay Youhnovski, Franziska Prömm, Markus Schirle, Michael Schumm, Ralph S. Pero, Alfred Doyle, James Checkel, Hirohito Kita, Nethaji Thiyagarajan, K. Ravi Acharya, Peter Schmid-Grendelmeier, Hans Uwe Simon, Heinz Schwarz, Masato Tsutsui, Hiroaki Shimokawa, Gabriel Bellon, James J. Lee, Michael PrzybylskiGerd Döring

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Nitration of tyrosine residues has been observed during various acute and chronic inflammatory diseases. However, the mechanism of tyrosine nitration and the nature of the proteins that become tyrosine nitrated during inflammation remain unclear. Here we show that eosinophils but not other cell types including neutrophils contain nitrotyrosine-positive proteins in specific granules. Furthermore, we demonstrate that the human eosinophil toxins, eosinophil peroxidase (EPO), major basic protein, eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), and the respective murine toxins, are post-translationally modified by nitration at tyrosine residues during cell maturation. High resolution affinity-mass spectrometry identified specific single nitration sites at Tyr349 in EPO and Tyr33 in both ECP and EDN. ECP and EDN crystal structures revealed and EPO structure modeling suggested that the nitrated tyrosine residues in the toxins are surface exposed. Studies in EPO-/-, gp91phox-/-, and NOS-/- mice revealed that tyrosine nitration of these toxins is mediated by EPO in the presence of hydrogen peroxide and minute amounts of NOx. Tyrosine nitration of eosinophil granule toxins occurs during maturation of eosinophils, independent of inflammation. These results provide evidence that post-translational tyrosine nitration is unique to eosinophils.

Original languageEnglish (US)
Pages (from-to)28629-28640
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number42
DOIs
StatePublished - Oct 17 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ulrich, M., Petre, A., Youhnovski, N., Prömm, F., Schirle, M., Schumm, M., Pero, R. S., Doyle, A., Checkel, J., Kita, H., Thiyagarajan, N., Acharya, K. R., Schmid-Grendelmeier, P., Simon, H. U., Schwarz, H., Tsutsui, M., Shimokawa, H., Bellon, G., Lee, J. J., ... Döring, G. (2008). Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase. Journal of Biological Chemistry, 283(42), 28629-28640. https://doi.org/10.1074/jbc.M801196200