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

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 identified the transcription factor THAP1, the causative gene of DYT6 dystonia, as a regulator of proteasome activity through genome-wide genetic screens. We demonstrated that THAP1 directly regulates the expression of the PSMB5 gene, which encodes the central protease subunit 5. Depletion of THAP1 disrupted proteasome assembly, leading to reduced proteasome activity and the accumulation of ubiquitinated proteins. These findings reveal a new regulatory mechanism for the proteasome and suggest a potential role for proteasome dysfunction in the pathogenesis of dystonia. RNA-Seq for THAP1C54Y/C54Y embryo and control embryo at e10.5蛋白酶体（proteasome）在蛋白质降解过程中发挥核心作用，其功能受损与包括神经退行性疾病在内的多种病理状态密切相关。现有研究已明确，Nrf1（Nrf1）可介导响应蛋白酶体功能障碍的所有蛋白酶体基因的诱导表达。然而，调控蛋白酶体基础转录水平的分子机制仍有待阐明。本研究通过全基因组遗传筛选，鉴定出DYT6型肌张力障碍（DYT6 dystonia）的致病基因——转录因子THAP1（THAP1）为蛋白酶体活性的调控因子。实验证实，THAP1可直接调控编码核心蛋白酶亚基5的PSMB5基因的表达。THAP1的敲除会破坏蛋白酶体的组装过程，导致蛋白酶体活性降低以及泛素化蛋白的积累。上述发现揭示了蛋白酶体调控的全新机制，并提示蛋白酶体功能障碍在肌张力障碍的发病机制中具有潜在作用。本研究对胚胎发育第10.5天（e10.5）的THAP1C54Y/C54Y突变胚胎与对照胚胎开展了RNA测序（RNA-Seq）实验。