CD95-tyrosine nitration inhibits hyperosmotic and CD95 ligand-induced CD95 activation in rat hepatocytes

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 H?ussinger, 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.     

PSD-95与神经精神疾病

PSD-95（postsynaptic density protein 95）是在兴奋性突触后密集区中纯化鉴定出的一种脚手架蛋白。通过PDZ（1-3）、SH3和GK结构域,PSD-95募集多种信号分子,在谷氨酸受体的信号整合和转导中具有关键性作用。PSD-95的功能异常与多种神经精神疾病密切相关,是多种重大脑病防治的新的药物作用靶点。     

The role of CD95 and CD95 ligand in cancer

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.     

Lipid signaling in CD95-mediated apoptosis.

Ceramides play an important role mediating different cell responses such as proliferation, differentiation, growth arrest and apoptosis. They are released upon sphingomyelin hydrolysis which occurs after triggering of a number of cell surface receptors including CD95. Ceramide generation also regulates glycosphingolipid and ganglioside metabolism. In particular, ganglioside GD3 biosynthesis represents an important event for the progression of apoptotic signals generated by CD95 and mediated by ceramide in hematopoietic cells.