Parkin promotes proteasomal degradation of misregulated BAX
Parkin promotes proteasomal degradation of misregulated BAX
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DOI：
10.1242/jcs.200162
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发表时间：
2017-09-01
影响因子：
4
通讯作者：
Edlich, Frank
中科院分区：
文献类型：
--
作者：
Cakir, Zeynep;Funk, Kathrin;Edlich, Frank
促凋亡 BCL-2 蛋白 BAX 通过透化线粒体外膜使人类细胞发生凋亡。 BAX 激活被认为需要将螺旋 a5 与 α 6 分离，即“闩锁”与“核心”结构域的分离，以及其他构象变化。在这里，我们表明该区域的构象变化会损害 BAX 向线粒体的易位和逆向易位回到胞质溶胶，从而损害 BAX 抑制，但不会激活。将失调的 BAX 重定向至线粒体揭示了 BAX 抑制的替代机制。 E3 连接酶 Parkin 已知可触发线粒体特异性自噬，泛素化 BAX K128 并靶向促凋亡 BCL-2 蛋白进行蛋白酶体降解。逆转录转位缺陷的 BAX 以 Parkin 依赖性方式完全降解。尽管只有一小部分内源性 BAX 逃脱了逆向易位进入细胞质，但线粒体上错误调节的 BAX 的 Parkin 依赖性靶向提供了针对 BAX 凋亡活性的实质性保护。
The pro-apoptotic BCL-2 protein BAX commits human cells to apoptosis by permeabilizing the outer mitochondrial membrane. BAX activation has been suggested to require the separation of helix a5 from alpha 6 -the 'latch' from the 'core' domain -among other conformational changes. Here, we show that conformational changes in this region impair BAX translocation to the mitochondria and retrotranslocation back into the cytosol, and therefore BAX inhibition, but not activation. Redirecting misregulated BAX to the mitochondria revealed an alternative mechanism of BAX inhibition. The E3 ligase parkin, which is known to trigger mitochondria-specific autophagy, ubiquitylates BAX K128 and targets the pro-apoptotic BCL-2 protein for proteasomal degradation. Retrotranslocation-deficient BAX is completely degraded in a parkin-dependent manner. Although only a minor pool of endogenous BAX escapes retrotranslocation into the cytosol, parkin-dependent targeting of misregulated BAX on the mitochondria provides substantial protection against BAX apoptotic activity.