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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Main Authors: Phuong Thao Ly, Ye Sing Tan, Chwee Tat Koe, Yingjie Zhang, Gengqiang Xie, Sharyn Endow, Wu-Min Deng, Fengwei Yu, Hongyan Wang
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2019-06-01
Series:PLoS Biology
Online Access:https://doi.org/10.1371/journal.pbio.3000276
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spelling 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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