AMPK/Ulk1-dependent autophagy as a key mTOR regulator in the context of cell pluripotency

摘要

The mechanisms providing high-quality control ofintracellular components are critical in embryonic development and, accordingly, must be highly effective inembryonic stem cells (ESCs) generating all types of adulttissues. Recently, it has been shown that defective ESCs inembryogenesis are eliminated from the populationthrough the mammalian target of rapamycin (mTOR)/p53mechanism1. Defective ESCs are the cells that, in responseto differentiation stimuli, are not able to exit from pluripotency, remaining undifferentiated. The underlyingreason for the resistance to differentiation is dysregulationof signal transduction pathways leading to the mTORpathway activation1. The mTOR pathway induces proteinsynthesis and cell growth in response to mitogenic signaling in the presence of high nutrient/energy levels andlow stress. The deletion of the mtor gene results inembryonic lethality shortly after implantation, indicating itspivotal role in differentiation2. Based on this the pluripotency establishment in vivo occurs in the absence of themTOR pathway but requires autophagy activation that isan antagonist of the mTOR activity. Autophagy is suppressed in oocytes but it is massively induced in a shorttime after fertilization3. At the same time, maternal proteins and organelles rapidly degrade and are replaced byembryonic genome-derived proteins, and consequentlyfertilized oocyte undergoes a large-scale intracellular rearrangement in a process called maternal-to-zygotic transition. Autophagy is responsible for this degradation, becauseit allows carrying out of large-scale restructuring of intracellular components by generating enough amino acids fornewly synthesized proteins, in particular pluripotencyassociated (PA) proteins. A key role of autophagy in thehomeostasis of ESCs has already established. It was shownthat autophagy regulates the levels of PA such as Oct4,Sox2, Nanog, and Klf4, and quantitative imbalances ofthese affect differentiation potential of cells4. Therefore,disturbance of autophagy may be crucial for the development of differentiation-resistant cells and their inclusion inthe final ESC- or induced pluripotent stem cell (iPSC)-derived cell product that will produce tumors after transplantation. Observed loss of the mTOR activity indifferentiation-resistant cells can be linked to persistentautophagy, being a barrier to exit from pluripotency.