CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation
CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation
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DOI：
10.1038/cdd.2014.194
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发表时间：
2015-06-01
影响因子：
12.4
通讯作者：
Zhang, Y.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Clegg, H. V.;Zhang, Y.
线粒体外膜透化（MOMP）是细胞凋亡过程中的一个关键控制点，导致细胞色素c等促凋亡线粒体内容物的释放。MOMP在很大程度上受Bcl-2家族蛋白如Bax控制，其在各种凋亡应激下被激活并在线粒体外膜上寡聚化。Bax寡聚化有助于促进线粒体内容物扩散到细胞质中，从而激活胱天蛋白酶级联反应。反过来，Bax主要由包括Bcl-xL在内的抗凋亡Bcl-2蛋白调节，最近显示Bcl-xL可防止Bax在线粒体处积累。然而，Bcl-xL调节Bax从而调节MOMP的确切机制仍不完全清楚。在这项研究中，我们表明，小CHCH结构域的蛋白CHCHD 2结合Bcl-xL和抑制线粒体的积累和Bax的寡聚化。我们的数据表明，在响应凋亡刺激，线粒体CHCHD 2减少之前MOMP。此外，当线粒体中不存在CHCHD 2时，Bcl-xL抑制Bax活化和防止细胞凋亡的能力减弱，这导致Bax寡聚化、MOMP和细胞凋亡增加。总的来说，我们的研究结果建立了CHCHD 2，一个以前没有特征的小线粒体蛋白，与Bcl-2家族没有已知的同源性，作为一个负调节器的细胞凋亡。
Mitochondrial outer membrane permeabilization (MOMP) is a critical control point during apoptosis that results in the release of pro-apoptotic mitochondrial contents such as cytochrome c. MOMP is largely controlled by Bcl-2 family proteins such as Bax, which under various apoptotic stresses becomes activated and oligomerizes on the outer mitochondrial membrane. Bax oligomerization helps promote the diffusion of the mitochondrial contents into the cytoplasm activating the caspase cascade. In turn, Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL, which was recently shown to prevent Bax from accumulating at the mitochondria. However, the exact mechanisms by which Bcl-xL regulates Bax and thereby MOMP remain partially understood. In this study, we show that the small CHCH-domain-containing protein CHCHD2 binds to Bcl-xL and inhibits the mitochondrial accumulation and oligomerization of Bax. Our data show that in response to apoptotic stimuli, mitochondrial CHCHD2 decreases prior to MOMP. Furthermore, when CHCHD2 is absent from the mitochondria, the ability of Bcl-xL to inhibit Bax activation and to prevent apoptosis is attenuated, which results in increases in Bax oligomerization, MOMP and apoptosis. Collectively, our findings establish CHCHD2, a previously uncharacterized small mitochondrial protein with no known homology to the Bcl-2 family, as one of the negative regulators of mitochondria-mediated apoptosis.