The Dependence Receptor TrkC Triggers Mitochondria-Dependent Apoptosis upon Cobra-1 Recruitment

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• 作者：Gabriel Ichim ; Anne-Laure Genevois ; Marie M¨¦nard ; Li-Ying Yu ; Juliana?M. Coelho-Aguiar ; Fabien Llambi ; Loraine Jarrosson-Wuilleme ; Jonathan Lefebvre ; David Tulasne ; Elisabeth Dupin ; Nicole Le?Douarin ; Urmas Arum?e ; Servane Tauszig-Delamasure ; Patrick Mehlen
• 刊名：Molecular Cell
• 出版年：2013
• 出版时间：12 September, 2013
• 年：2013
• 卷：51
• 期：5
• 页码：632-646
• 全文大小：2884 K

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Summary

The neurotrophin receptor TrkC was recently identified as a dependence receptor, and, as such, it triggers apoptosis in the absence of its ligand, NT-3. The molecular mechanism for apoptotic engagement involves the double cleavage of the receptor¡¯s intracellular domain, leading to the formation of a proapoptotic ¡°killer¡± fragment (TrkC KF). Here, we show that TrkC KF interacts with Cobra1, a putative cofactor of BRCA1, and that Cobra1 is required for TrkC-induced apoptosis. We also show that, in the developing chick neural tube, NT-3 silencing is associated with neuroepithelial cell death that is rescued by Cobra1 silencing. Cobra1 shuttles TrkC KF to the mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. Thus, we propose that, in the absence of NT-3, the proteolytic cleavage of TrkC leads to the release of a killer fragment that triggers mitochondria-dependent apoptosis via the recruitment of Cobra1.