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. 2015 Jun;17(6):715-25.
doi: 10.1038/ncb3172. Epub 2015 May 18.

Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming

Yasong Wu  1 , Yuan Li  2 , Hui Zhang  1 , Yinghua Huang  1 , Ping Zhao  1 , Yujia Tang  1 , Xiaohui Qiu  1 , Yue Ying  1 , Wen Li  3 , Su Ni  1 , Meng Zhang  4 , Longqi Liu  1 , Yan Xu  1 , Qiang Zhuang  1 , Zhiwei Luo  1 , Christina Benda  1 , Hong Song  1 , Baohua Liu  5 , Liangxue Lai  1 , Xingguo Liu  1 , Hung-Fat Tse  6 , Xichen Bao  1 , Wai-Yee Chan  7 , Miguel A Esteban  8 , Baoming Qin  8 , Duanqing Pei  8
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Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming

Yasong Wu et al. Nat Cell Biol. 2015 Jun.

Abstract

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.

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