Powering stem cell decisions with ubiquitin.
Powering stem cell decisions with ubiquitin.
复制标题
利用泛素为干细胞决策提供动力。
DOI：
10.1038/cdd.2017.142
复制
发表时间：
2017
影响因子：
12.4
通讯作者：
Rape,Michael
中科院分区：
文献类型：
--
作者：
Werner,Achim;Rape,Michael
自我更新的小鼠胚胎干细胞（mESCs）含有很少的线粒体，在分化开始时线粒体的数量和体积增加。KBP（由kif1bp编码）是线粒体相关激酶Kif1Bα的相互作用因子。我们发现，在mESCs中，负责线粒体乙酰辅酶a生成的TDH和乙酰转移酶GCN5L1协同作用，使KBP中的Lys501乙酰化，允许其通过Fbxo15识别和降解，Fbxo15是一种由多能性核心因子转录控制的F-box蛋白，并在分化后受到抑制。mESCs中KBP降解缺陷导致线粒体生物发生意外增加，呼吸和ROS产生增强，以及细胞增殖抑制。Kif1Bα的沉默逆转了KBP稳定诱导的线粒体的异常增加。值得注意的是，分化后，Kif1bp−/−mESCs表现出线粒体质量扩张受损，形成更小的胚状体。因此，KBP蛋白水解限制了mESCs中线粒体的积累，以保持其最佳适应性，而KBP积累促进了分化细胞中线粒体的生物发生。
Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded byKif1bp) is an interactor of the mitochondrial-associated kinesin Kif1Bα. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation. Defects in KBP degradation in mESCs result in an unscheduled increase in mitochondrial biogenesis, enhanced respiration and ROS production, and inhibition of cell proliferation. Silencing of Kif1Bα reverts the aberrant increase in mitochondria induced by KBP stabilization. Notably, following differentiation,Kif1bp−/−mESCs display impaired expansion of the mitochondrial mass and form smaller embryoid bodies. Thus, KBP proteolysis limits the accumulation of mitochondria in mESCs to preserve their optimal fitness, whereas KBP accumulation promotes mitochondrial biogenesis in differentiating cells.