Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling

Hao Gu, Qidong Li, Shan Huang, Weiguang Lu, Fangyuan Cheng, Ping Gao, Chen Wang, Lin Miao, Yide Mei, Mian Wu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number7112
JournalNature Communications
Volume6
DOIs
StatePublished - Jun 2 2015
Externally publishedYes

Fingerprint

Ubiquitin-Protein Ligases
stem cells
Stem cells
mice
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
retarding
Embryonic Stem Cells
cells
Intrinsic Factor
organisms
serums
inhibitors
Serum
Mouse Embryonic Stem Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling. / Gu, Hao; Li, Qidong; Huang, Shan; Lu, Weiguang; Cheng, Fangyuan; Gao, Ping; Wang, Chen; Miao, Lin; Mei, Yide; Wu, Mian.

In: Nature Communications, Vol. 6, 7112, 02.06.2015.

Research output: Contribution to journalArticle

Gu, H, Li, Q, Huang, S, Lu, W, Cheng, F, Gao, P, Wang, C, Miao, L, Mei, Y & Wu, M 2015, 'Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling', Nature Communications, vol. 6, 7112. https://doi.org/10.1038/ncomms8112
Gu, Hao ; Li, Qidong ; Huang, Shan ; Lu, Weiguang ; Cheng, Fangyuan ; Gao, Ping ; Wang, Chen ; Miao, Lin ; Mei, Yide ; Wu, Mian. / Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling. In: Nature Communications. 2015 ; Vol. 6.
@article{c035f51ea3324e11b701ade1d7cc921d,
title = "Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling",
abstract = "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.",
author = "Hao Gu and Qidong Li and Shan Huang and Weiguang Lu and Fangyuan Cheng and Ping Gao and Chen Wang and Lin Miao and Yide Mei and Mian Wu",
year = "2015",
month = "6",
day = "2",
doi = "10.1038/ncomms8112",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84931291926&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931291926&partnerID=8YFLogxK

U2 - 10.1038/ncomms8112

DO - 10.1038/ncomms8112

M3 - Article

C2 - 26033541

AN - SCOPUS:84931291926

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 7112

ER -