CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation.
The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily con...
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doaj-e95abb8a797e4b4599072337cfefff5b2021-06-24T04:32:53ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-06-01176e300027610.1371/journal.pbio.3000276CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation.Phuong Thao LyYe Sing TanChwee Tat KoeYingjie ZhangGengqiang XieSharyn EndowWu-Min DengFengwei YuHongyan WangThe ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.https://doi.org/10.1371/journal.pbio.3000276 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Phuong Thao Ly Ye Sing Tan Chwee Tat Koe Yingjie Zhang Gengqiang Xie Sharyn Endow Wu-Min Deng Fengwei Yu Hongyan Wang |
spellingShingle |
Phuong Thao Ly Ye Sing Tan Chwee Tat Koe Yingjie Zhang Gengqiang Xie Sharyn Endow Wu-Min Deng Fengwei Yu Hongyan Wang CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. PLoS Biology |
author_facet |
Phuong Thao Ly Ye Sing Tan Chwee Tat Koe Yingjie Zhang Gengqiang Xie Sharyn Endow Wu-Min Deng Fengwei Yu Hongyan Wang |
author_sort |
Phuong Thao Ly |
title |
CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. |
title_short |
CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. |
title_full |
CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. |
title_fullStr |
CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. |
title_full_unstemmed |
CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. |
title_sort |
crl4mahj e3 ubiquitin ligase promotes neural stem cell reactivation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2019-06-01 |
description |
The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain. |
url |
https://doi.org/10.1371/journal.pbio.3000276 |
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