Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules.
Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules.
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DOI：
10.1083/jcb.201210045
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发表时间：
2013-06-24
期刊：
影响因子：
--
通讯作者：
Cribbs JT
中科院分区：
文献类型：
--
作者：
Strack S;Wilson TJ;Cribbs JT
剪接异构体Drp 1-x 01促进线粒体分裂，并受微管相关的Cdk磷酸化依赖性变化的调节。分裂和融合反应决定线粒体的形态和功能。动力蛋白相关蛋白1（Drp 1）是一种三磷酸鸟苷水解酶，对线粒体分裂和程序性细胞死亡很重要。drp 1是受三个外显子的选择性剪接与以前未知的功能意义。在这里，我们报告，剪接变体，包括第三，但不包括第二个选择性外显子（x 01）本地化和copurified与微管束作为动态聚合物，类似于线粒体上的裂变复合物。作为免疫细胞中的主要亚型，Drp 1-x 01需要寡聚体组装和选择性外显子3中的Arg残基用于微管靶向。drp 1-x 01稳定和捆绑微管和衰减staurosporine诱导的线粒体片段化和凋亡。微管结合外显子附近的保守Ser残基的磷酸化从微管释放Drp 1-x 01，并以剪接形式特异性的方式促进线粒体片段化。Cdk 1的磷酸化导致Drp 1-x 01从有丝分裂微管中解离，而Cdk 5介导的磷酸化调节Drp 1-x 01靶向间期微管。因此，选择性剪接产生一个潜在的，细胞骨架池的Drp 1是选择性动员细胞周期蛋白依赖性激酶信号。
The splice isoform Drp1-x01 promotes mitochondrial fission and is regulated by Cdk phosphorylation-dependent changes in microtubule association. Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling.
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影响因子：
9.8
作者：
Merrill RA;Dagda RK;Dickey AS;Cribbs JT;Green SH;Usachev YM;Strack S
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影响因子：
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作者：
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通讯作者：
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