Marini E S, Giampietri C, Petrungaro S, Conti S, Filippini A, Scorrano L, Ziparo E
Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
1] Department of Biology, University of Padua, Padua, Italy [2] Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.
Cell Death Differ. 2015 Jul;22(7):1131-43. doi: 10.1038/cdd.2014.197. Epub 2014 Dec 12.
Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in c-FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4.
死亡受体介导途径的组分，如半胱天冬酶 - 8，已在细胞内膜的复合物中被鉴定出来，以在空间上限制局部靶标的加工。在本研究中，我们报道了细胞FLICE抑制蛋白（c-FLIP(L)）的长亚型，一种众所周知的外源性细胞死亡起始半胱天冬酶 - 8的抑制剂，定位于内质网（ER）和线粒体相关膜（MAM）。在c-FLIP(-/-)小鼠胚胎成纤维细胞（MEF）中，ER形态受到破坏，ER钙释放以及ER-线粒体连接减少。从机制上讲，c-FLIP缺失导致基础半胱天冬酶 - 8激活增强，以及半胱天冬酶介导的内质网塑形蛋白网织蛋白 - 4（RTN4）的加工，通过重新引入c-FLIP(L)和半胱天冬酶抑制得以纠正，从而恢复正常的ER形态和ER-线粒体并列。因此，半胱天冬酶 - 8抑制剂c-FLIP(L)作为MAM信号平台的一个组分出现，在该平台中，半胱天冬酶似乎通过作用于像RTN4这样的内质网塑形蛋白来调节ER形态和ER-线粒体串扰。
