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

• DOI: 10.1038/s41467-025-56867-x
• Publication Date: 2025-02-14T10:02:10Z
• Authors: 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; Shigeo Murata
• Keywords: Protein Degradation

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