2. Academic Validation
  3. Inhibition of deubiquitinase USP28 attenuates cyst growth in autosomal dominant polycystic kidney disease

Inhibition of deubiquitinase USP28 attenuates cyst growth in autosomal dominant polycystic kidney disease

  • Biochem Pharmacol. 2022 Nov 25;115355. doi: 10.1016/j.bcp.2022.115355.
Ying Ren 1,  Xiaodan Zhu 1,  Kequan Fu 1,  Haoran Zhang 1,  Wenchao Zhao 1,  Yang Lin 1,  Qian Fang 2,  Junqi Wang 2,  Yupeng Chen 3,  Dong Guo 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China.
  • 2 The Affiliated Hospital of Xuzhou Medical University, No. 99 Huaihai West Road, Xuzhou 221002, China.
  • 3 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300070, China. Electronic address: ychen@tmu.edu.cn.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China. Electronic address: guo@xzhmu.edu.cn.
PMID: 36442624 DOI: 10.1016/j.bcp.2022.115355
Abstract

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.

Keywords

ADPKD; STAT3; USP28; c-Myc; cystogenesis.

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