The DYT6 dystonia causative protein THAP1 is responsible for proteasome activity via PSMB5 transcriptional regulation

Yan Wang, Yi Wang, Tomohiro Iriki, Eiichi Hashimoto, Maki Inami, Sota Hashimoto, Ayako Watanabe, Hiroshi Takano, Ryo Motosugi, Shoshiro Hirayama, Hiroki Sugishita, Yukiko Gotoh, Ryoji Yao, Jun Hamazaki and Shigeo Murata (smurata@g.ecc.u-tokyo.ac.jp)
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Yan Wang: the University of Tokyo
Yi Wang: the University of Tokyo
Tomohiro Iriki: the University of Tokyo
Eiichi Hashimoto: the University of Tokyo
Maki Inami: the University of Tokyo
Sota Hashimoto: the University of Tokyo
Ayako Watanabe: the University of Tokyo
Hiroshi Takano: Japanese Foundation for Cancer Research
Ryo Motosugi: the University of Tokyo
Shoshiro Hirayama: the University of Tokyo
Hiroki Sugishita: the University of Tokyo
Yukiko Gotoh: the University of Tokyo
Ryoji Yao: Japanese Foundation for Cancer Research
Jun Hamazaki: the University of Tokyo
Shigeo Murata: the University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The proteasome plays a pivotal role in protein degradation, and its impairment is associated with various pathological conditions, including neurodegenerative diseases. It is well understood that Nrf1 coordinates the induction of all proteasome genes in response to proteasome dysfunction. However, the molecular mechanism regulating the basal expression of the proteasome remains unclear. Here we identify the transcription factor THAP1, the causative gene of DYT6 dystonia, as a regulator of proteasome activity through a genome-wide genetic screen. We demonstrated that THAP1 directly regulates the expression of the PSMB5 gene, which encodes the central protease subunit β5. Depletion of THAP1 disrupts proteasome assembly, leading to reduced proteasome activity and the accumulation of ubiquitinated proteins. These findings uncover a regulatory mechanism for the proteasome and suggest a potential role for proteasome dysfunction in the pathogenesis of dystonia.

Date: 2025
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DOI: 10.1038/s41467-025-56867-x

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