RRC ID 57363
Author Ly PT, Tan YS, Koe CT, Zhang Y, Xie G, Endow S, Deng WM, Yu F, Wang H.
Title CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation.
Journal PLoS Biol
Abstract 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.
Volume 17(6)
Pages e3000276
Published 2019-6-1
DOI 10.1371/journal.pbio.3000276
PMID 31170139
PMC PMC6553684
MeSH Animals Animals, Genetically Modified / metabolism Carrier Proteins / metabolism* Carrier Proteins / physiology Cullin Proteins / metabolism DNA-Binding Proteins / metabolism DNA-Binding Proteins / physiology Drosophila Proteins / metabolism* Drosophila Proteins / physiology Drosophila melanogaster / metabolism Humans Neural Stem Cells / metabolism* Protein Binding / physiology Signal Transduction / physiology Ubiquitin-Protein Ligase Complexes / metabolism Ubiquitin-Protein Ligases / metabolism* Ubiquitin-Protein Ligases / physiology Ubiquitination
IF 8.386
Times Cited 3
Drosophila DGRC#108418