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Cited by 6Ubiquitin and proteasome pathwaysHeat shock proteins researchProtein Degradation and Inhibitors

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Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression

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Ramage, Dylan E., Grant, Drew W., Timms, Richard T.·2025·Nature Communications
DOI 10.1038/s41467-025-56782-1PMC PMC11811203

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Abstract

The 26S proteasome is a multi-catalytic protease that serves as the endpoint for protein degradation via the ubiquitin-proteasome system. Proteasome function requires the concerted activity of 33 distinct gene products, but how the expression of proteasome subunits is regulated in mammalian cells remains poorly understood. Leveraging coessentiality data from the DepMap project, here we characterize an essential role for the dystonia gene THAP1 in maintaining the basal expression of PSMB5 . PSMB5 insufficiency resulting from loss of THAP1 leads to defects in proteasome assembly, impaired proteostasis and cell death. Exploiting the fact that the toxicity associated with loss of THAP1 can be rescued upon exogenous expression of PSMB5, we define the transcriptional targets of THAP1 through RNA-seq analysis and perform a deep mutational scan to systematically assess the function of thousands of single amino acid THAP1 variants. Altogether, these data identify THAP1 as a critical regulator of proteasome function and suggest that aberrant proteostasis may contribute to the pathogenesis of THAP1 dystonia.

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Metadata

Authors
Ramage, D. E., Grant, D. W., & Timms, R. T.
Affiliations
University of Cambridge (GB)
Corresponding author
Timms, Richard T.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-10
Volume
16
Issue
1
Pages
1511-1511
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-56782-1
PMC
PMC11811203
OpenAlex
W4407358693
Cited by
6
References
3
Citations by year
2026: 4 · 2025: 2
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Academy of Medical Sciences (SBF007\100019)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
THAP1, PSMB5, 26S proteasome, proteasome assembly, ubiquitin-proteasome system, proteostasis, loss-of-function mutations, dystonia, deep mutational scanning, transcriptional regulation, protein degradation
MeSH terms
Loss of Function Mutation, Proteostasis, Animals, DNA-Binding Proteins, Dystonia, Humans, Proteasome Endopeptidase Complex, Apoptosis Regulatory Proteins, HEK293 Cells

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