2. Academic Validation
  3. Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage

Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage

  • Cell Death Dis. 2024 Sep 9;15(9):660. doi: 10.1038/s41419-024-07042-5.
Martin D Burkhalter 1,  Tom Stiff 2,  Lars D Maerz 3,  Teresa Casar Tena 3,  Heike Wiese 4,  Julian Gerhards 1,  Steffen A Sailer 1,  Linh Anna Trúc Vu 1,  Max Duong Phu 1,  Cornelia Donow 3,  Marius Alupei 5,  Sebastian Iben 5,  Marco Groth 6,  Sebastian Wiese 4,  Joseph A Church 7,  Penelope A Jeggo 2,  Melanie Philipp 8
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, 72074, Tübingen, Germany.
  • 2 Genome Damage and Stability Centre, University of Sussex, Brighton, BN1 9RQ, UK.
  • 3 Institute for Biochemistry and Molecular Biology, Ulm University, 89081, Ulm, Germany.
  • 4 Core Unit Mass Spectrometry and Proteomics, Medical Faculty, Ulm University, 89081, Ulm, Germany.
  • 5 Department of Dermatology, Ulm University, 89081, Ulm, Germany.
  • 6 Core Facility Next Generation Sequencing, Leibniz Institute on Aging-Fritz Lipmann Institute, 07745, Jena, Germany.
  • 7 Department of Pediatrics, Keck School of Medicine of University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, 90033, USA.
  • 8 Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, 72074, Tübingen, Germany. melanie.philipp@uni-tuebingen.de.
PMID: 39251572 DOI: 10.1038/s41419-024-07042-5
Abstract

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.

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