IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation
IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation
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DOI：
10.1038/emboj.2010.39
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发表时间：
2010-04-21
期刊：
影响因子：
11.4
通讯作者：
Karbowski, Mariusz
中科院分区：
文献类型：
--
作者：
Benard, Giovanni;Neutzner, Albert;Karbowski, Mariusz
Bax是一种来自Bcl-2家族的促凋亡蛋白，是凋亡调节的核心。为了抑制自发性凋亡，Bax必须处于严格的控制之下，这可能包括Bax构象和表达水平的调节。我们报告，IBRDC2，IBR型环指E3泛素连接酶，调节Bax的水平，并保护细胞免受自发Bax激活和细胞死亡。IBRDC2的下调诱导增加的细胞水平和Bax的活性形式的积累。在健康细胞和凋亡细胞中，Bax稳定性的遍在化依赖性调节受到IBRDC2下调的抑制，并受到IBRDC2过表达的刺激。虽然在健康细胞中主要是胞浆的，但在诱导凋亡后，IBRDC2在富含Bax的线粒体结构域中积累。IBRDC2的线粒体积累与Bax激活平行发生，并且还取决于Bcl-xL的表达水平。此外，IBRDC2与活化的Bax物理相互作用。通过在HCT 116 Bax（-/-）细胞中应用Bax突变体，结合使用活性Bax特异性抗体，我们已经确定线粒体定位和Bax的细胞凋亡激活是IBRDC2转运到线粒体所必需的。The EMBO Journal（2010）29，1458 - 1471. doi：10.1038/doj.2010.39; 2010年3月18日在线发布
Bax, a pro-apoptotic protein from the Bcl-2 family, is central to apoptosis regulation. To suppress spontaneous apoptosis, Bax must be under stringent control that may include regulation of Bax conformation and expression levels. We report that IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase, regulates the levels of Bax and protects cells from unprompted Bax activation and cell death. Downregulation of IBRDC2 induces increased cellular levels and accumulation of the active form of Bax. The ubiquitination-dependent regulation of Bax stability is suppressed by IBRDC2 downregulation and stimulated by IBRDC2 overexpression in both healthy and apoptotic cells. Although mostly cytosolic in healthy cells, upon induction of apoptosis, IBRDC2 accumulates in mitochondrial domains enriched with Bax. Mitochondrial accumulation of IBRDC2 occurs in parallel with Bax activation and also depends on the expression levels of Bcl-xL. Furthermore, IBRDC2 physically interacts with activated Bax. By applying Bax mutants in HCT116 Bax(-/-) cells, combined with the use of active Bax-specific antibodies, we have established that both mitochondrial localization and apoptotic activation of Bax are required for IBRDC2 translocation to the mitochondria. The EMBO Journal (2010) 29, 1458-1471. doi: 10.1038/emboj.2010.39; Published online 18 March 2010