RRC ID 33964
Author Wu Y, Li Y, Zhang H, Huang Y, Zhao P, Tang Y, Qiu X, Ying Y, Li W, Ni S, Zhang M, Liu L, Xu Y, Zhuang Q, Luo Z, Benda C, Song H, Liu B, Lai L, Liu X, Tse HF, Bao X, Chan WY, Esteban MA, Qin B, Pei D.
Title Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming.
Journal Nat Cell Biol
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.
Volume 17(6)
Pages 715-25
Published 2015-6-1
DOI 10.1038/ncb3172
PII ncb3172
PMID 25985393
MeSH Animals Apoptosis Regulatory Proteins / genetics Autophagy / genetics* Autophagy-Related Protein 5 Beclin-1 Cells, Cultured Cellular Reprogramming / genetics* Class III Phosphatidylinositol 3-Kinases / genetics Down-Regulation Fibroblasts / cytology Induced Pluripotent Stem Cells / cytology* Kruppel-Like Factor 4 Kruppel-Like Transcription Factors / metabolism Mechanistic Target of Rapamycin Complex 1 Mice Mice, Knockout Microtubule-Associated Proteins / genetics Mitochondria / genetics Mitochondria / metabolism* Multiprotein Complexes / antagonists & inhibitors Multiprotein Complexes / biosynthesis Multiprotein Complexes / metabolism* Octamer Transcription Factor-3 / metabolism Proto-Oncogene Proteins c-myc / metabolism RNA Interference RNA, Small Interfering SOXB1 Transcription Factors / metabolism TOR Serine-Threonine Kinases / antagonists & inhibitors TOR Serine-Threonine Kinases / biosynthesis TOR Serine-Threonine Kinases / metabolism* Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism
IF 20.042
Times Cited 49
Mice RBRC02231