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J. Biol. Chem., Vol. 279, Issue 11, 10364-10373, March 12, 2004

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CD95-tyrosine Nitration Inhibits Hyperosmotic and CD95 Ligand-induced CD95 Activation in Rat Hepatocytes^*

Roland Reinehr, Boris Görg, Andrea Höngen, and Dieter Häussinger

From the Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany

Epidermal growth factor receptor-dependent CD95-tyrosine phosphorylation was recently identified as an early step in apoptosis induction via the CD95 system (Reinehr, R., Schliess, F., and Häussinger, D. (2003) FASEB J. 17, 731–733). The effect of peroxynitrite (ONOO^-) on modulation of the hyperosmotic and CD95 ligand (CD95L)-induced CD95 activation process was studied. Pretreatment of hepatocytes with ONOO^- inhibited CD95L- and hyperosmolarity-induced CD95 membrane trafficking and formation of the death-inducing signaling complex, but not epidermal growth factor receptor activation and its association with CD95. Under these conditions, however, no tyrosine phosphorylation of CD95 occurred; instead, CD95 was tyrosine-nitrated. When ONOO^- was added after induction of CD95-tyrosine phosphorylation by CD95L or hyperosmolarity, tyrosine nitration of CD95 was largely prevented and death-inducing signaling complex formation occurred. CD95-tyrosine nitration abolished the hyperosmotic sensitization of hepatocytes toward CD95L-induced apoptosis. Additionally, in CD95-yellow fluorescent protein-transfected Huh7-hepatoma cells, ONOO^- induced CD95 Tyr nitration and prevented CD95L-induced Tyr phosphorylation and apoptosis. Tyrosine-nitrated CD95 was also found in rat livers derived from an in vivo model of endotoxinemia. The data suggest that CD95-tyrosine nitration prevents CD95 activation by inhibiting CD95-tyrosine phosphorylation. Apparently, CD95-tyrosine phosphorylation and nitration are mutually exclusive. The data identify critical tyrosine residues of CD95 as another target of the anti-apoptotic action of NO.

Received for publication, November 3, 2003 , and in revised form, December 15, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Sonderforschungsbereich 575 "Experimentelle Hepatologie" (Düsseldorf). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Moorenstr. 5, D-40225 Düsseldorf, Germany. Tel.: 49-211-811-7569; Fax: 49-211-811-8838; E-mail: haeussin{at}uni-duesseldorf.de.

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