Deubiquitinase inhibitor bAP-15 suppresses renal epithelial to mesenchymal transition via inhibition of p300 stability

• Published in: Biochemical and biophysical research communications 2024-12, Vol.741, p.151095, Article 151095
• Main Authors: Kim, Hyunsik, Kim, Hyunseung, Lee, Sun-Ho, Kwon, Jae-Hwan, Byun, Seunghee, Yoo, Jung-Yoon, Park, Soo-Yeon, Yoon, Ho-Geun
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - metabolism; Epithelial-Mesenchymal Transition - drug effects; Epithelial-to-mesenchymal transition; Fibrosis; Histone acetyltransferase p300; Humans; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Mice; Mice, Inbred C57BL; Protein Stability - drug effects; Pyrroles; Pyrrolidines; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Ubiquitin C-Terminal hydrolase L5; Ubiquitin specific peptidase 14; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.151095

Renal fibrosis is an irreversible disease that is common in patients with chronic kidney disease. Elevated levels of the histone acetyltransferase p300 have been reported in various fibrotic diseases, including renal fibrosis, suggesting that p300 may be a promising therapeutic target. To investigate the specific deubiquitinase (DUB) involved in the regulation of p300 protein stability in renal epithelial cells, we tested 13 DUB inhibitors using a kidney tubular epithelial cell line. We found that the p300-specific DUB inhibitor, bAP-15 reduces p300 protein stability by targeting ubiquitin-specific protease 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5). The mRNA levels of USP14 and UCHL5 were increased in patients with chronic kidney disease, and increased protein levels of USP14 and UCHL5 during fibrosis progression were validated using a mouse renal fibrosis model. Both USP14 and UCHL5 interacted with p300 in kidney tubular epithelial cells, with increased binding affinity in response to TGF-β. Moreover, bAP-15-induced p300 degradation inhibited epithelial-to-mesenchymal transition and reduced the expression of pro-fibrotic target genes. Our findings demonstrate an anti-fibrotic effect of bAP-15 through the regulation of p300 stability and suggest that bAP-15 may be a potential therapeutic agent for renal fibrosis. •USP14 and UCHL5 are upregulated in the kidneys of CKD patients and UUO mouse model.•The USP14/UCHL5 inhibitor bAP-15 reduces p300 protein levels by inhibiting deubiquitination.•BAP-15 suppresses epithelial-to-mesenchymal transition and the expression of fibrosis-related genes.