N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development
Zhihua Ma # 1, Yi Zeng # 1, Ming Wang # 1,
Wei Liu 1, Jiafeng Zhou 1, Chao Wu 1, Lin Hou 1 2, Bin Yin 1 2, Boqin Qiang 1
2, Pengcheng Shu 1 2 3, Xiaozhong Peng 1 4 5
EMBO J.2023 Oct 9:e113383. doi:
10.15252/embj.2022113383.
PMID: 37807845
Abstract
Notch
signaling pathway activity, particularly fluctuations in the biologically
active effector fragment NICD, is required for rapid and efficient dynamic
regulation of proper fate decisions in stem cells. In this study, we identified
NEDD4-binding protein 1 (N4BP1), which is highly expressed in the developing
mouse cerebral cortex, as a negative modulator of Notch signaling dynamics in
neural progenitor cells. Intriguingly, N4BP1 regulated NICD stability
specifically after Notch1 S3 cleavage through ubiquitin-mediated degradation
that depended on its RAM domain, not its PEST domain, as had been extensively
and previously described. The CoCUN domain in N4BP1, particularly the
"Phe-Pro" motif (862/863 amino acid), was indispensable for mediating
NICD degradation. The Ring family E3 ligase Trim21 was, in contrast to other
NEDD4 family members, required for N4BP1-regulated NICD degradation.
Overexpression of N4BP1 in cortical neural progenitors promoted neural stem
cell differentiation, whereas neural progenitor cells lacking N4BP1 were
sensitized to Notch signaling, resulting in the maintenance of stem-like
properties in neural progenitor cells and lower production of cortical neurons.