CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation

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 CRL4 Mahj , 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 CRL4 Mahj 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 CRL4 Mahj 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.

Msps Governs Acentrosomal Microtubule Assembly and Reactivation of Quiescent Neural Stem Cells

“…In the absence of nutrition, the hippo pathway inactivates Yokie to maintain the quiescence of NSCs (Ding et al, 2016;Poon et al, 2016). The hippo pathway is inactivated in response to dietary amino acids and is downregulated by the CRL4-Mahjong E3 ligase complex (Ly et al, 2019).…”

Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders

“…The protein turnover of Lats/Warts, a core protein kinase in the Hippo pathway, is regulated by a Cullin-really interesting new gene (RING) ligase named CRL4 Mahjong , an evolutionarily conserved E3 ubiquitin ligase composed of Cullin4 (Cul4), DNA damage-binding protein 1 (DDB1), regulator of cullins-1 (Roc1), and a substrate receptor named Mahjong [149]. Both DDB1 and Mahjong are up-regulated in reactivated NSCs compared with quiescent NSCs and are required for NSC reactivation [149]. Depletion of ddb1 or mahjong in NSCs leads to delayed NSC reactivation and a microcephaly-like phenotype [149].…”

“…Both DDB1 and Mahjong are up-regulated in reactivated NSCs compared with quiescent NSCs and are required for NSC reactivation [149]. Depletion of ddb1 or mahjong in NSCs leads to delayed NSC reactivation and a microcephaly-like phenotype [149]. CRL4 Mahjong targets Warts for ubiquitination and degradation, therefore releasing Yorkie into the nucleus to trigger NSC reactivation [149].…”

“…Depletion of ddb1 or mahjong in NSCs leads to delayed NSC reactivation and a microcephaly-like phenotype [149]. CRL4 Mahjong targets Warts for ubiquitination and degradation, therefore releasing Yorkie into the nucleus to trigger NSC reactivation [149]. The interaction between CRL4 and Warts/Lats is conserved because in human cancer cells, CRL4 E3 ligase activity is increased, leading to the ubiquitination and down-regulation of Lats1/2 [150].…”

Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

“…Our observation that Hippo pathway activity controls Kib levels in a Yki-independent manner suggests that Kib could be regulated post-translationally. Protein abundance is commonly regulated by phosphorylation-dependent ubiquitination, and multiple Hippo pathway components are regulated via ubiquitin-mediated proteasomal degradation (Ribeiro et al, 2014;Rodrigues-Campos and Thompson, 2014;Cao et al, 2014;Aerne et al, 2015;Ma et al, 2018;Ly et al, 2019). Since a kinase cascade is at the core of the Hippo pathway, we hypothesized that Hippo pathway activity could promote Kib phosphorylation and target it for ubiquitination and subsequent degradation.…”