Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport.
Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport.
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DOI：
10.3389/fphys.2017.00905
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发表时间：
2017
影响因子：
4
通讯作者：
Shaw RM
中科院分区：
文献类型：
--
作者：
Fu Y;Zhang SS;Xiao S;Basheer WA;Baum R;Epifantseva I;Hong T;Shaw RM
连接蛋白43（Cx43，由GJA 1编码）是在所有器官系统中表达的细胞-细胞通信间隙连接蛋白。最近发现，GJA 1 mRNA经历交替翻译以产生N-末端截短的同种型，其中GJA 1 - 20 k是最丰富的。在这里，我们报告了一个令人惊讶的发现，与全长GJA 1 - 43 k不同，GJA 1 - 20 k对线粒体具有很强的向性。探索功能，我们发现GJA 1 - 20 k似乎是一种细胞器伴侣，并且GJA 1 - 20 k的过表达足以在暴露于过氧化氢时拯救线粒体定位到细胞外周，这有效地限制了氧化应激发生的网络碎片化。通过高分辨率荧光成像和电子显微镜，我们确定GJA 1 - 20 k在线粒体和微管之间的界面富集，似乎装载细胞器进行运输。突变实验表明，尽管GJA 1 - 20 k中的微管结合结构域（MTBD）对于蛋白质定位于线粒体不是必需的，但MTBD对于GJA 1 - 20 k促进线粒体运输和维持线粒体在外周的定位是必需的。这些结果揭示了Cx43间隙连接蛋白GJA 1 - 20 k的替代翻译同种型的意想不到的作用，其促进基于微管的线粒体运输并在细胞应激期间维持线粒体网络的完整性。
Connexin 43 (Cx43, encoded by GJA1) is a cell-cell communication gap junction protein expressed in all organ systems. It was recently found that GJA1 mRNA undergoes alternative translation to generate N-terminal truncated isoforms, of which GJA1-20k is the most abundant. Here we report a surprising finding that, unlike full length GJA1-43k, GJA1-20k has a strong tropism for mitochondria. Exploring function, we found that GJA1-20k appears to be an organelle chaperone and that overexpression of GJA1-20k is sufficient to rescue mitochondrial localization to the cell periphery upon exposure to hydrogen peroxide, which effectively limits the network fragmentation that occurs with oxidative stress. By high-resolution fluorescent imaging and electron microscopy, we determined that GJA1-20k is enriched at the interface between mitochondria and microtubules, appearing to load organelles for transport. Mutagenesis experiments revealed that although the microtubule-binding domain (MTBD) in GJA1-20k is not necessary for protein localization to mitochondria, the MTBD is essential for GJA1-20k to facilitate mitochondrial transport and maintain mitochondrial localization at the periphery. These results reveal an unexpected role for the alternatively translated isoform of the Cx43 gap junction protein, GJA1-20k, which is to facilitate microtubule-based mitochondrial transport and to maintain mitochondrial network integrity during cellular stress.
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影响因子：
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