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

Author

Listed:
  • Yan Wang

    (the University of Tokyo
    The Affiliated Kangning Hospital of Ningbo University)

  • 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
    the University of Tokyo)

  • Yukiko Gotoh

    (the University of Tokyo
    the University of Tokyo)

  • Ryoji Yao

    (Japanese Foundation for Cancer Research)

  • Jun Hamazaki

    (the University of Tokyo)

  • Shigeo Murata

    (the University of Tokyo)

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.

Suggested Citation

  • 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 , 2025. "The DYT6 dystonia causative protein THAP1 is responsible for proteasome activity via PSMB5 transcriptional regulation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56867-x
    DOI: 10.1038/s41467-025-56867-x
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    References listed on IDEAS

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    1. Yuko Hirano & Klavs B. Hendil & Hideki Yashiroda & Shun-ichiro Iemura & Ryoichi Nagane & Yusaku Hioki & Tohru Natsume & Keiji Tanaka & Shigeo Murata, 2005. "A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes," Nature, Nature, vol. 437(7063), pages 1381-1385, October.
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