Ubiquitylation is required for the incorporation of the Notch receptor into intraluminal vesicles to prevent prolonged and ligand-independent activation of the pathway.
Dx
E3-ligase
Endocytosis
Itch
Notch signalling
Su(dx)
Ubiquitylation
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
10 03 2022
10 03 2022
Historique:
received:
07
10
2021
accepted:
01
02
2022
entrez:
10
3
2022
pubmed:
11
3
2022
medline:
15
4
2022
Statut:
epublish
Résumé
Ubiquitylation of the ligands and the receptor plays an important part in the regulation of the activity of the evolutionary conserved Notch signalling pathway. However, its function for activation of Notch is not completely understood, despite the identification of several E3 ligases devoted to the receptor. Here we analysed a variant of the Notch receptor where all lysines in its intracellular domain are replaced by arginines. Our analysis of this variant revealed that ubiquitylation of Notch is not essential for its endocytosis. We identified two functions for ubiquitylation of lysines in the Notch receptor. First, it is required for the degradation of free Notch intracellular domain (NICD) in the nucleus, which prevents a prolonged activation of the pathway. More importantly, it is also required for the incorporation of Notch into intraluminal vesicles of maturing endosomes to prevent ligand-independent activation of the pathway from late endosomal compartments. The findings clarify the role of lysine-dependent ubiquitylation of the Notch receptor and indicate that Notch is endocytosed by several independent operating mechanisms.
Sections du résumé
BACKGROUND
Ubiquitylation of the ligands and the receptor plays an important part in the regulation of the activity of the evolutionary conserved Notch signalling pathway. However, its function for activation of Notch is not completely understood, despite the identification of several E3 ligases devoted to the receptor.
RESULTS
Here we analysed a variant of the Notch receptor where all lysines in its intracellular domain are replaced by arginines. Our analysis of this variant revealed that ubiquitylation of Notch is not essential for its endocytosis. We identified two functions for ubiquitylation of lysines in the Notch receptor. First, it is required for the degradation of free Notch intracellular domain (NICD) in the nucleus, which prevents a prolonged activation of the pathway. More importantly, it is also required for the incorporation of Notch into intraluminal vesicles of maturing endosomes to prevent ligand-independent activation of the pathway from late endosomal compartments.
CONCLUSIONS
The findings clarify the role of lysine-dependent ubiquitylation of the Notch receptor and indicate that Notch is endocytosed by several independent operating mechanisms.
Identifiants
pubmed: 35264151
doi: 10.1186/s12915-022-01245-y
pii: 10.1186/s12915-022-01245-y
pmc: PMC8908686
doi:
Substances chimiques
Drosophila Proteins
0
Ligands
0
Receptors, Notch
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
65Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/C503162/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/E002285/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H000976/1
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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