美国宾夕法尼亚大学Xiaolu Yang研究组近日取得一项新成果。他们发现伴侣蛋白介导的自噬调节胚胎干细胞的多能性。2020年7月24日出版的《科学》杂志发表了这项成果。

他们显示核心多能性因子OCT4和SOX2抑制伴侣介导的自噬（CMA），这是自噬的一种选择性形式，持续到分化开始。低CMA活性促进胚胎干细胞自我更新，而其上调则促进分化。CMA降解异柠檬酸脱氢酶IDH1和IDH2，并降低细胞内α-酮戊二酸水平，α-酮戊二酸是参与多能性的各种组蛋白和DNA去甲基酶的强制性辅因子。

这些发现表明，CMA介导了核心多能性因子对代谢的影响，塑造了干细胞的表观遗传格局，并控制了自我更新与分化之间的平衡。

据悉，胚胎干细胞可以以多能状态无限期繁殖，当回复到胚胎时，能够分化为所有类型的特化细胞。在繁殖过程中什么维持它们的多能性还不清楚。

附：英文原文

Title: Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells

Author: Yi Xu, Yang Zhang, Juan C. García-Caaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian A. Blair, Joshua D. Rabinowitz, Xiaolu Yang

Issue&Volume: 2020/07/24

Abstract: Embryonic stem cells can propagate indefinitely in a pluripotent state, able to differentiate into all types of specialized cells when restored to the embryo. What sustains their pluripotency during propagation remains unclear. Here, we show that core pluripotency factors OCT4 and SOX2 suppress chaperone-mediated autophagy (CMA), a selective form of autophagy, until the initiation of differentiation. Low CMA activity promotes embryonic stem cell self-renewal, whereas its up-regulation enhances differentiation. CMA degrades isocitrate dehydrogenases IDH1 and IDH2 and reduces levels of intracellular α-ketoglutarate, an obligatory cofactor for various histone and DNA demethylases involved in pluripotency. These findings suggest that CMA mediates the effect of core pluripotency factors on metabolism, shaping the epigenetic landscape of stem cells and governing the balance between self-renewal and differentiation.

DOI: 10.1126/science.abb4467

Source: https://science.sciencemag.org/content/369/6502/397