Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
1] Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China [2] School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Nat Cell Biol. 2015 Jun;17(6):715-25. doi: 10.1038/ncb3172. Epub 2015 May 18.
We describe robust induction of autophagy during the reprogramming of mouse fibroblasts to induced pluripotent stem cells by four reprogramming factors (Sox2, Oct4, Klf4 and c-Myc), henceforth 4F. This process occurs independently of p53 activation, and is mediated by the synergistic downregulation of mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy-related genes. The 4F coordinately repress mTORC1, but bifurcate in their regulation of autophagy-related genes, with Klf4 and c-Myc inducing them but Sox2 and Oct4 inhibiting them. On one hand, inhibition of mTORC1 facilitates reprogramming by promoting cell reshaping (mitochondrial remodelling and cell size reduction). On the other hand, mTORC1 paradoxically impairs reprogramming by triggering autophagy. Autophagy does not participate in cell reshaping in reprogramming but instead degrades p62, whose accumulation in autophagy-deficient cells facilitates reprogramming. Our results thus reveal a complex signalling network involving mTORC1 inhibition and autophagy induction in the early phase of reprogramming, whose delicate balance ultimately determines reprogramming efficiency.
我们描述了在通过四个重编程因子（Sox2、Oct4、Klf4 和 c-Myc）将小鼠成纤维细胞重编程为诱导多能干细胞的过程中，自噬的强烈诱导。这个过程独立于 p53 的激活，由机械靶蛋白雷帕霉素复合物 1（mTORC1）的协同下调和自噬相关基因的诱导介导。4F 共同抑制 mTORC1，但在调节自噬相关基因方面存在分歧，Klf4 和 c-Myc 诱导它们，而 Sox2 和 Oct4 抑制它们。一方面，通过促进细胞重塑（线粒体重塑和细胞大小减少），抑制 mTORC1 促进了重编程。另一方面，mTORC1 通过触发自噬反而损害了重编程。自噬不参与重编程中的细胞重塑，而是降解 p62，p62 在自噬缺陷细胞中的积累促进了重编程。因此，我们的结果揭示了在重编程早期阶段涉及 mTORC1 抑制和自噬诱导的复杂信号网络，其微妙的平衡最终决定了重编程效率。
