PMID- 34866316
OWN - NLM
STAT- MEDLINE
DCOM- 20220314
LR  - 20230204
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 23
IP  - 2
DP  - 2022 Feb 3
TI  - The mTORC1-eIF4F axis controls paused pluripotency.
PG  - e53081
LID - 10.15252/embr.202153081 [doi]
LID - e53081
AB  - Mouse embryonic stem cells (mESCs) can self-renew indefinitely and maintain 
      pluripotency. Inhibition of mechanistic target of rapamycin (mTOR) by the kinase 
      inhibitor INK128 is known to induce paused pluripotency in mESCs cultured with 
      traditional serum/LIF medium (SL), but the underlying mechanisms remain unclear. 
      In this study, we demonstrate that mTOR complex 1 (mTORC1) but not complex 2 
      (mTORC2) mediates mTOR inhibition-induced paused pluripotency in cells grown in 
      both SL and 2iL medium (GSK3 and MEK inhibitors and LIF). We also show that 
      mTORC1 regulates self-renewal in both conditions mainly through eIF4F-mediated 
      translation initiation that targets mRNAs of both cytosolic and mitochondrial 
      ribosome subunits. Moreover, inhibition of mitochondrial translation is 
      sufficient to induce paused pluripotency. Interestingly, eIF4F also regulates 
      maintenance of pluripotency in an mTORC1-independent but MEK/ERK-dependent manner 
      in SL, indicating that translation of pluripotency genes is controlled 
      differently in SL and 2iL. Our study reveals a detailed picture of how mTOR 
      governs self-renewal in mESCs and uncovers a context-dependent function of eIF4F 
      in pluripotency regulation.
CI  - (c) 2021 The Authors.
FAU - Xu, Xueting
AU  - Xu X
AUID- ORCID: 0000-0002-8011-7449
AD  - School of Life Sciences, University of Science and Technology of China, Hefei, 
      China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Ahmed, Tanveer
AU  - Ahmed T
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Wang, Lulu
AU  - Wang L
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Cao, Xintao
AU  - Cao X
AD  - Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of 
      Sciences, Beijing, China.
FAU - Zhang, Zeyu
AU  - Zhang Z
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
FAU - Wang, Ming
AU  - Wang M
AD  - Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, 
      Department of Biochemistry & Molecular Biology, Shenzhen University Health 
      Science Center, Shenzhen, China.
FAU - Lv, Yuan
AU  - Lv Y
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
AD  - Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Kanwal, Shahzina
AU  - Kanwal S
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Tariq, Muqddas
AU  - Tariq M
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
FAU - Lin, Runxia
AU  - Lin R
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Zhang, Hui
AU  - Zhang H
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
FAU - Huang, Yinghua
AU  - Huang Y
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Peng, Hao
AU  - Peng H
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Lin, Danni
AU  - Lin D
AD  - School of Life Sciences, University of Science and Technology of China, Hefei, 
      China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
FAU - Shi, Xue
AU  - Shi X
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Geng, Didi
AU  - Geng D
AD  - MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life 
      Sciences, Zhejiang University, Hangzhou, China.
FAU - Liu, Baohua
AU  - Liu B
AUID- ORCID: 0000-0002-1599-8059
AD  - Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, 
      Department of Biochemistry & Molecular Biology, Shenzhen University Health 
      Science Center, Shenzhen, China.
FAU - Zhang, Xiaofei
AU  - Zhang X
AUID- ORCID: 0000-0002-2564-9258
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Yi, Wen
AU  - Yi W
AD  - MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life 
      Sciences, Zhejiang University, Hangzhou, China.
FAU - Qin, Yan
AU  - Qin Y
AUID- ORCID: 0000-0003-0391-1005
AD  - Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of 
      Sciences, Beijing, China.
FAU - Esteban, Miguel A
AU  - Esteban MA
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
AD  - Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing, 
      China.
AD  - Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health and 
      Guangzhou Medical University, Guangzhou, China.
FAU - Qin, Baoming
AU  - Qin B
AUID- ORCID: 0000-0001-7652-161X
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell 
      and Regenerative Medicine Research Center, Guangzhou Institutes of Biomedicine 
      and Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Laboratory of Metabolism and Cell Fate, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, China.
AD  - Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong 
      Laboratory), Guangzhou, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
AD  - Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health and 
      Guangzhou Medical University, Guangzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211206
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - 0 (Eukaryotic Initiation Factor-4F)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Animals
MH  - *Eukaryotic Initiation Factor-4F/genetics
MH  - *Mechanistic Target of Rapamycin Complex 1/genetics
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mouse Embryonic Stem Cells/*cytology
MH  - Pluripotent Stem Cells/*cytology
PMC - PMC8811634
OTO - NOTNLM
OT  - eIF4F
OT  - mTORC1
OT  - mitochondrial translation
OT  - pluripotency
OT  - self-renewal
COIS- The authors declare that they have no conflict of interest.
EDAT- 2021/12/07 06:00
MHDA- 2022/03/15 06:00
PMCR- 2023/02/03
CRDT- 2021/12/06 06:15
PHST- 2021/11/01 00:00 [revised]
PHST- 2021/04/17 00:00 [received]
PHST- 2021/11/16 00:00 [accepted]
PHST- 2021/12/07 06:00 [pubmed]
PHST- 2022/03/15 06:00 [medline]
PHST- 2021/12/06 06:15 [entrez]
PHST- 2023/02/03 00:00 [pmc-release]
AID - EMBR202153081 [pii]
AID - 10.15252/embr.202153081 [doi]
PST - ppublish
SO  - EMBO Rep. 2022 Feb 3;23(2):e53081. doi: 10.15252/embr.202153081. Epub 2021 Dec 6.