Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage
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.
Authors
- Martin D. Burkhalter (ORCID: https://orcid.org/0000-0002-8646-3131)
- Marco Groth (ORCID: https://orcid.org/0000-0002-9199-8990)
- Heike Wiese (ORCID: https://orcid.org/0000-0002-8941-3762)
- Julian Gerhards (ORCID: https://orcid.org/0000-0002-7005-1618)
- Sebastian Wiese (ORCID: https://orcid.org/0000-0001-5697-2608)
- Melanie Philipp (ORCID: https://orcid.org/0000-0003-2714-965X)
- Sebastian Iben (ORCID: https://orcid.org/0000-0002-5207-2861)
- Teresa Casar Tena
- Tom Stiff
- Cornelia Donow
- Marius Costel Alupei
- Penny A. Jeggo (ORCID: https://orcid.org/0000-0002-8481-1462)
- Max Duong Phu
- Joseph A. Church
- Steffen A Sailer (ORCID: https://orcid.org/0000-0002-3804-0986)
- Linh Anna Trúc Vu
- Lars D. Maerz
Institutions
- Children's Hospital of Los Angeles (US)
- University of Sussex (GB)
- Universität Ulm (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- PharmacoGenetics (China) (CN)
- University Hospital Ulm (DE)
- Technische Hochschule Ulm (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41419-024-07042-5
- Citations
- 1
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.55
Funders
- Fundació la Marató de TV3
- University of Sussex
- Deutsche Forschungsgemeinschaft
- Universität Ulm