Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
09 Sep 2024
09 Sep 2024
Historique:
received:
03
02
2024
accepted:
29
08
2024
revised:
07
08
2024
medline:
10
9
2024
pubmed:
10
9
2024
entrez:
9
9
2024
Statut:
epublish
Résumé
The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.
Identifiants
pubmed: 39251572
doi: 10.1038/s41419-024-07042-5
pii: 10.1038/s41419-024-07042-5
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ubiquitin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
660Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : PH144/4-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : PH144/4-3
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : PH144/6-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 467868420
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1074
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1074
Informations de copyright
© 2024. The Author(s).
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