Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
Autophagy. 2023 Feb;19(2):544-550. doi: 10.1080/15548627.2022.2083857. Epub 2022 Jun 1.
The aggregation of mutant HTT (huntingtin; mHTT) is a hallmark of Huntington disease (HD). mHTT aggregates interact and sequester dozens of proteins and affect diverse key cellular functions. Here we report that TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, is yet another protein that co-aggregates with mHTT. We also found the mHTT-TFEB co-aggregation is mediated by a prion-like domain (PrLD) near the N terminus of TFEB. Our findings point out a possible limitation for therapeutic strategies targeting TFEB to clear mHTT, and also provided a possible explanation for controversies that TFEB overexpression lowered soluble mHTT in some HD models but failed to reduce mHTT aggregates or HD pathology in others. Moreover, we found that TFE3, another MiT family transcription factor that shares overlapping functions with TFEB, lacks PrLD and does not co-aggregate with mHTT, and thus might serve as an alternative drug target for HD.
突变 HTT（亨廷顿蛋白；mHTT）的聚集是亨廷顿病（HD）的一个标志。mHTT 聚集物相互作用并隔离数十种蛋白质，并影响多种关键细胞功能。在这里，我们报告转录因子 EB（TFEB），溶酶体生物发生和自噬的主要调节剂，是另一种与 mHTT 共聚集的蛋白质。我们还发现 mHTT-TFEB 共聚集是由 TFEB 近 N 端的类朊病毒结构域（PrLD）介导的。我们的发现指出了针对 TFEB 清除 mHTT 的治疗策略的一个可能限制，也为 TFEB 过表达在一些 HD 模型中降低可溶性 mHTT 但未能降低 mHTT 聚集物或 HD 病理学的争议提供了一个可能的解释。此外，我们发现另一种 MiT 家族转录因子 TFE3 缺乏 PrLD，也不与 mHTT 共聚集，它与 TFEB 具有重叠的功能，因此可能是 HD 的另一个药物靶点。
