A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1
A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1
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DOI：
10.1016/j.cellsig.2013.07.016
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发表时间：
2013-11-01
影响因子：
4.8
通讯作者：
Tang, Jie
中科院分区：
文献类型：
--
作者：
Wang, Peng;Wu, Yanfang;Tang, Jie
内质网（endoplasmic reticulum，ER）正常功能的紊乱可导致内质网腔内未折叠蛋白的积累和Ca 2+调节的紊乱，并引起一系列复杂的反应，称为未折叠蛋白反应（unfolded protein response，UPR），其最初目的是重建内环境的稳定和正常生理，但如果UPR不能补偿损伤，则最终可引发细胞死亡。在这里，我们表明，ER定位人环指E3连接酶RNF 186参与ER应激介导的细胞凋亡的过程。RNF 186的过表达可刺激Hela细胞中ER传感器蛋白的上调和ER Ca 2+的快速传递，而RNF 186的敲低则表现出对ER应激的中等程度的抵抗，表明RNF 186可在ER引起应激信号传导。我们进一步鉴定了Bcl-2家族蛋白BNip 1作为RNF 186的底物之一。BNip 1与RNF 186共定位于ER，并在体内通过K29和K63连接被RNF 186多聚泛素化。这种修饰促进BNip 1转运到线粒体，但对其蛋白水平没有影响。RNF 186在内质网应激下的半衰期延长，可能是因为其自身泛素化和随后的蛋白酶体降解受到抑制。此外，BNip 1的泛素化在内质网应激时大大增强，可能是由于RNF 186的积累。更重要的是，BNip 1的敲低减弱了RNF 186诱导的ER应激信号。这些结果共同表明，BNip 1作为RNF 186的下游调节剂发挥作用，以指导ER应激相关的凋亡信号传导。我们的研究可能揭示了一种新的E3连接酶介导的调节ER应激的机制。(C)2013 Elsevier Inc. All rights reserved.
Disturbances in the normal functions of the endoplasmic reticulum (ER) can lead to the accumulation of unfolded proteins and disturbance of Ca2+ regulation within the lumen of ER, and arouse a series of complicated response termed unfolded protein response (UPR), which is aimed initially at reestablishing homeostasis and normal physiology but can ultimately trigger cell death if the UPR fails to compensate for damage. Here we show that ER locating human RING finger E3 ligase RNF186 participates in the process of ER stress-mediated apoptosis. Overexpression of RNF186 stimulates upregulation of ER sensor proteins and rapid transmission of ER Ca2+ in Hela cells, while RNF186 knockdown exhibits a moderate degree of resistance to ER stress, indicating RNF186 can arouse stress signaling at ER. We further identified the Bcl-2 family protein BNip1 as one of the substrates of RNF186. BNip1 co-localizes with RNF186 at ER and is poly-ubiquitinated by RNF186 through K29 and K63 linkage in vivo. This modification promotes BNip1 transportation to mitochondria but has no influence on its protein level. The half-life of RNF186 is prolonged under ER stress, probably because of the inhibition on its self-ubiquitination and subsequent degradation by proteasomes. In addition, the ubiquitination of BNip1 is greatly enhanced when ER stress occurred, possibly due to RNF186 accumulation. More importantly, knockdown of BNip1 attenuates the stress signals at ER induced by RNF186. These results collectively indicate that BNip1 functions as a downstream modulator of RNF186 to direct ER stress-associated apoptotic signaling. Our study might reveal a novel E3 ligase-mediated mechanism for modulating ER stress. (C) 2013 Elsevier Inc. All rights reserved.