TY - JOUR
T1 - Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling
AU - Gu, Hao
AU - Li, Qidong
AU - Huang, Shan
AU - Lu, Weiguang
AU - Cheng, Fangyuan
AU - Gao, Ping
AU - Wang, Chen
AU - Miao, Lin
AU - Mei, Yide
AU - Wu, Mian
N1 - Funding Information:
This work was supported by grants from the Chinese Academy of Sciences (XDA01020104); Ministry of Science and Technology of China (2011CB966302); National Natural Science Foundation of China (31371388 and 81101525); Natural Science Foundation of Anhui Province (1408085J07) and the Fundamental Research Funds For Central Universities (WK2070000034).
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/6/2
Y1 - 2015/6/2
N2 - Embryonic stem cells (ESCs) possess pluripotency, which is the capacity of cells to differentiate into all lineages of the mature organism. Increasing evidence suggests that the pluripotent state of ESCs is regulated by a combination of extrinsic and intrinsic factors. The underlying mechanisms, however, are not completely understood. Here, we show that March5, an E3 ubiquitin ligase, is involved in maintaining mouse-ESC (mESC) pluripotency. Knockdown of March5 in mESCs led to differentiation from naive pluripotency. Mechanistically, as a transcriptional target of Klf4, March5 catalyses K63-linked polyubiquitination of Prkar1a, a negative regulatory subunit of PKA, to activate PKA, thereby inhibiting the Raf/MEK/ERK pathway. Moreover, March5 is able to replace a MEK/ERK inhibitor to maintain mESC pluripotency under serum-free culture conditions. In addition, March5 can partially replace the use of Klf4 for somatic cell reprogramming. Collectively, our study uncovers a role for the Klf4-March5-PKA-ERK pathway in maintaining the stemness properties of mESCs.
AB - Embryonic stem cells (ESCs) possess pluripotency, which is the capacity of cells to differentiate into all lineages of the mature organism. Increasing evidence suggests that the pluripotent state of ESCs is regulated by a combination of extrinsic and intrinsic factors. The underlying mechanisms, however, are not completely understood. Here, we show that March5, an E3 ubiquitin ligase, is involved in maintaining mouse-ESC (mESC) pluripotency. Knockdown of March5 in mESCs led to differentiation from naive pluripotency. Mechanistically, as a transcriptional target of Klf4, March5 catalyses K63-linked polyubiquitination of Prkar1a, a negative regulatory subunit of PKA, to activate PKA, thereby inhibiting the Raf/MEK/ERK pathway. Moreover, March5 is able to replace a MEK/ERK inhibitor to maintain mESC pluripotency under serum-free culture conditions. In addition, March5 can partially replace the use of Klf4 for somatic cell reprogramming. Collectively, our study uncovers a role for the Klf4-March5-PKA-ERK pathway in maintaining the stemness properties of mESCs.
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U2 - 10.1038/ncomms8112
DO - 10.1038/ncomms8112
M3 - Article
C2 - 26033541
AN - SCOPUS:84931291926
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7112
ER -