Galichet Arnaud, Weibel Mirjam, Heizmann Claus W
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
Biochem Biophys Res Commun. 2008 May 23;370(1):1-5. doi: 10.1016/j.bbrc.2008.02.163. Epub 2008 Mar 18.
The receptor for advanced glycation endproducts (RAGE) interacts with several ligands and is involved in various human diseases. RAGE_v1 or sRAGE, a RAGE splice variant, is secreted and contributes to the removal of RAGE ligands. Because RAGE blockade by specific antibodies directed against RAGE extracellular domains and the use of sRAGE have been proven to be beneficial in the context of pathological settings, both RAGE and sRAGE are considered as therapeutic target. Here, we show that sRAGE is also produced through regulated intramembrane proteolysis of the RAGE receptor, which is catalyzed by ADAM10 and the gamma-secretase and that calcium is an essential regulator of RAGE processing. Furthermore, RAGE intracellular domain localizes both in the cytoplasm and the nucleus and induces apoptosis when expressed in cells. These findings reveal new aspects of RAGE regulation and signaling and also provide a new interaction between RAGE and human pathologies.
晚期糖基化终末产物受体（RAGE）与多种配体相互作用，并参与多种人类疾病。RAGE_v1或sRAGE是RAGE的一种剪接变体，可分泌并有助于清除RAGE配体。由于针对RAGE细胞外结构域的特异性抗体阻断RAGE以及使用sRAGE已被证明在病理环境中有益，因此RAGE和sRAGE都被视为治疗靶点。在此，我们表明sRAGE也通过RAGE受体的调节性膜内蛋白水解产生，这一过程由ADAM10和γ-分泌酶催化，并且钙是RAGE加工的关键调节因子。此外，RAGE细胞内结构域定位于细胞质和细胞核中，并在细胞中表达时诱导细胞凋亡。这些发现揭示了RAGE调节和信号传导的新方面，也为RAGE与人类疾病之间提供了新的联系。
