Ren Ying, Zhu Xiaodan, Fu Kequan, Zhang Haoran, Zhao Wenchao, Lin Yang, Fang Qian, Wang Junqi, Chen Yupeng, Guo Dong
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China.
The Affiliated Hospital of Xuzhou Medical University, No. 99 Huaihai West Road, Xuzhou 221002, China.
Biochem Pharmacol. 2023 Jan;207:115355. doi: 10.1016/j.bcp.2022.115355. Epub 2022 Nov 25.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, which is characterized by progressive growth of multiple renal cysts in bilateral kidneys. In the past decades, mechanistic studies have entailed many essential signalling pathways that were regulated through post-translational modifications (PTMs) during cystogenesis. Among the numerous PTMs involved, the effect of ubiquitination and deubiquitination remains largely unknown. Herein, we identified that USP28, a deubiquitinase aberrantly upregulated in patients with ADPKD, selectively removed K48-linked polyubiquitination and reversed protein degradation of signal transducer and activator of transcription 3 (STAT3). We also observed that USP28 could directly interact with and stabilize c-Myc, a transcriptional target of STAT3. Both processes synergistically enhanced renal cystogenesis. Furthermore, pharmacological inhibition of USP28 attenuated the cyst formation both in vivo and in vitro. Collectively, USP28 regulates STAT3 turnover and its transcriptional target c-Myc in ADPKD. USP28 inhibition could be a novel therapeutic strategy against ADPKD.
常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾病，其特征是双侧肾脏中多个肾囊肿进行性生长。在过去几十年中，机制研究涉及了许多在囊肿形成过程中通过翻译后修饰（PTM）进行调节的重要信号通路。在众多涉及的PTM中，泛素化和去泛素化的作用在很大程度上仍不清楚。在此，我们发现USP28，一种在ADPKD患者中异常上调的去泛素酶，选择性地去除K48连接的多聚泛素化并逆转信号转导和转录激活因子3（STAT3）的蛋白质降解。我们还观察到USP28可以直接与STAT3的转录靶点c-Myc相互作用并使其稳定。这两个过程协同增强肾囊肿形成。此外，对USP28的药理学抑制在体内和体外均减弱了囊肿形成。总体而言，USP28在ADPKD中调节STAT3的周转及其转录靶点c-Myc。抑制USP28可能是一种针对ADPKD的新型治疗策略。
