ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins.
ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins.
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DOI：
10.7554/elife.06547
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发表时间：
2015-05-26
期刊：
影响因子：
7.7
通讯作者：
Martin-Serrano J
中科院分区：
文献类型：
--
作者：
Caballe A;Wenzel DM;Agromayor M;Alam SL;Skalicky JJ;Kloc M;Carlton JG;Labrador L;Sundquist WI;Martin-Serrano J
转运所需的内体分选复合物（ESCRT）机制介导了细胞动力学分离过程中子细胞之间的物理分离。这一过程受染色体断裂检查点的调节，这是一种依赖于Aurora B和ESCRT-III亚基CHMP 4C的基因组保护机制，以延迟响应染色体错误分离的断裂。在这项研究中，我们表明，Unc-51样激酶3（ULK 3）磷酸化和结合ESCRT-III亚基通过串联MIT域，从而延迟响应落后的染色体，核孔缺陷和张力在中间体的解离。我们的结构和生物化学研究揭示了ULK 3和IST 1之间异常紧密的相互作用，IST 1是一种ESCRT-III亚基，需要进行酶解。我们还表明，由ULK 3的IST 1磷酸化是维持解离检查点所需的重要信号，并且ULK 3和CHMP 4C是在多种生理情况下控制解离的计时器的功能相关的组件。DOI：http://dx.doi.org/10.7554/eLife.06547.001我们的细胞通过一分为二来繁殖。许多蛋白质参与了这一过程，包括一组称为ESCRT-III复合物。当两个新的子细胞周围的单膜分离时，这一组需要完成细胞分裂的最后阶段。在细胞分裂之前，它的DNA--被包装在称为染色体的结构中--被复制，两组染色体被拉到细胞的两端。这确保了每个子细胞都有一套完整的DNA。如果细胞在染色体完成向细胞两端移动之前分裂，子细胞可能会以错误的染色体数量结束。这可能导致癌症或其他疾病。为了防止这种情况，细胞已经进化出一种称为“分裂检查点”的质量控制系统，该系统延迟细胞分裂，直到染色体正确分离。先前的研究表明，当检查点处于活动状态时，一种名为CHMP 4C的ESCRT-III复合蛋白会被一种酶灭活，从而阻止细胞分裂。其他表明新的子细胞尚未准备好分离的信号也可以延迟细胞分裂，但目前尚不清楚检查点如何检测到这些缺陷。Caballe，Wenzel等人发现一种名为ULK 3的蛋白质可以与ESCRT-III复合物中的几种蛋白质结合，包括一种名为IST 1的蛋白质。在这样做的过程中，如果染色体尚未完成分离，如果细胞核中存在缺陷，或者如果细胞在膜分离的部位经历高水平的机械张力，ULK 3能够延迟细胞分裂。实验还表明，ULK 3需要结合并调节IST 1的活性以维持解离检查点，并且CHMP 4C是该过程所需的。Caballe，Wenzel等的发现揭示了ULK 3在控制细胞分裂时起着至关重要的作用，并暗示可能有额外的蛋白质参与释放ULK 3施加的检查点延迟细胞。接下来的挑战将是识别这些蛋白质，并了解所有检查点蛋白质如何共同调节细胞分裂。DOI：http://dx.doi.org/10.7554/eLife.06547.002网站
The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations. DOI: http://dx.doi.org/10.7554/eLife.06547.001 Our cells multiply by dividing into two. Many proteins are involved in this process, including a group called the ESCRT-III complex. This group is required to complete the final stage of cell division when the single membrane that surrounds the two new daughter cells separates. Before the cell divides, its DNA—which is packaged in structures called chromosomes—is copied, and the two sets of chromosomes are pulled to opposite ends of the cell. This ensures that each daughter cell will have a complete set of DNA. If the cell divides before the chromosomes have finished moving to opposite ends of the cell, the daughter cells may end up with the wrong number of chromosomes. This can lead to cancer or other diseases. To prevent this, cells have evolved a quality control system called the ‘abscission checkpoint’, which delays cell division until the chromosomes have properly separated. Previous studies have shown that when the checkpoint is active, an ESCRT-III complex protein called CHMP4C is inactivated by an enzyme, which prevents the cell from dividing. Other signals that indicate that the new daughter cells are not yet ready to separate can also delay cell division, but it is not clear how those defects are detected by the checkpoint. Here, Caballe, Wenzel et al. found that a protein called ULK3 can bind to several proteins in the ESCRT-III complex, including one called IST1. In doing so, ULK3 is able to delay cell division if the chromosomes have not finished separating, if there are defects in the nucleus of the cell, or if the cell is experiencing high levels of mechanical tension at the site where the membrane will separate. The experiments also show that ULK3 needs to bind to and regulate the activity of IST1 to sustain the abscission checkpoint, and that CHMP4C is required for this process. Caballe, Wenzel et al.'s findings reveal that ULK3 plays an essential role in controlling when a cell divides and imply that there may be additional proteins involved that release cells from the checkpoint delay imposed by ULK3. The next challenges will be to identify these proteins and to understand how all checkpoint proteins work together to regulate cell division. DOI: http://dx.doi.org/10.7554/eLife.06547.002