Transient Activation of Autophagy via Sox2-Mediated Suppression of mTOR Is an Important Early Step in Reprogramming to Pluripotency

• Autophagy is required for reprogramming to induced pluripotent stem cells
• Sox2 initiates autophagy by repressing mTOR expression early in reprogramming
• Subsequently, restoration of mTOR expression is required to complete reprogramming
• Sox2 binds to a repressor region in the mTOR promoter and recruits the NuRD complex

SummaryAutophagy is an essential cellular mechanism that degrades cytoplasmic proteins and organelles to recycle their components. Here we show that autophagy is required for reprogramming of somatic cells to form induced pluripotent stem cells (iPSCs). Our data indicate that mammalian target of rapamycin (mTOR) is downregulated by Sox2 at an early stage of iPSC generation and that this transient downregulation of mTOR is required for reprogramming to take place. In the absence of Sox2, mTOR remains at a high level and inhibits autophagy. Mechanistically, Sox2 binds to a repressive region on the mTOR promoter and recruits the NuRD complex to mediate transcriptional repression. We also detected enhanced autophagy at the four- to eight-cell stage of embryonic development, and a similar Sox2 and mTOR-mediated regulatory pathway seems to operate in this context as well. Thus, our findings reveal Sox2-dependent temporal regulation of autophagy as a key step in cellular reprogramming processes.

Graphical AbstractFigure optionsDownload high-quality image (185 K)Download as PowerPoint slide