Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin.
Axin degradation
D. melanogaster
Dishevelled
Naked/NKD
biochemistry
cell biology
chemical biology
feedback control
histidine cluster
p62 autophagy receptor
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
07 10 2020
07 10 2020
Historique:
received:
10
06
2020
accepted:
06
10
2020
pubmed:
8
10
2020
medline:
20
2
2021
entrez:
7
10
2020
Statut:
epublish
Résumé
Feedback control is a universal feature of cell signaling pathways. Naked/NKD is a widely conserved feedback regulator of Wnt signaling which controls animal development and tissue homeostasis. Naked/NKD destabilizes Dishevelled, which assembles Wnt signalosomes to inhibit the β-catenin destruction complex via recruitment of Axin. Here, we discover that the molecular mechanism underlying Naked/NKD function relies on its assembly into ultra-stable decameric core aggregates via its conserved C-terminal histidine cluster (HisC). HisC aggregation is facilitated by Dishevelled and depends on accumulation of Naked/NKD during prolonged Wnt stimulation. Naked/NKD HisC cores co-aggregate with a conserved histidine cluster within Axin, to destabilize it along with Dishevelled, possibly via the autophagy receptor p62, which binds to HisC aggregates. Consistent with this, attenuated Wnt responses are observed in CRISPR-engineered flies and human epithelial cells whose Naked/NKD HisC has been deleted. Thus, HisC aggregation by Naked/NKD provides context-dependent feedback control of prolonged Wnt responses.
Identifiants
pubmed: 33025907
doi: 10.7554/eLife.59879
pii: 59879
pmc: PMC7581431
doi:
pii:
Substances chimiques
Axin Protein
0
Axn protein, Drosophila
0
Drosophila Proteins
0
nkd protein, Drosophila
0
Histidine
4QD397987E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MC_U105192713
Pays : United Kingdom
Organisme : Medical Research Council
ID : U105192713
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C7379/A24639
Pays : United Kingdom
Informations de copyright
© 2020, Gammons et al.
Déclaration de conflit d'intérêts
MG, MR, JF, JM, MB No competing interests declared
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