Usp40, the ubiquitin-specific protease 40, is a deubiquitinating enzyme that plays significant roles in multiple biological processes. It is involved in pathways related to protein stability regulation by removing ubiquitin from target proteins, which is crucial for maintaining normal cellular functions. Genetic models, such as knockout (KO) mice, have been valuable in studying its functions [1,4].

In podocyte damage, USP40 knockout mice showed no abnormal kidney phenotype, but intermediate filament Nestin was upregulated in glomeruli. USP40 was found to deubiquitinate HINT1, an inducer of p53, and gene knockdown of USP40 in cultured podocytes reduced HINT1 and p53 protein expression. In FSGS, HINT1 upregulation preceded proteinuria, followed by upregulation of USP40, p53, and Nestin, suggesting USP40 contributes to podocyte hypertrophy in FSGS [1]. In zebrafish, knockdown of Usp40 led to disorganized glomeruli, reduced cell junctions in endothelium, foot-process effacement in podocytes, and disrupted glomerular permeability, indicating its role in glomerulogenesis and maintaining glomerular integrity after birth [4].

In hepatocellular carcinoma (HCC), USP40 knockdown inhibited HCC cell proliferation, migration, and stemness. USP40 interacts with YAP to maintain its stability and with Claudin1 to inhibit its polyubiquitination, promoting HCC progression, and a positive feedback loop between USP40 and YAP exists [2,3].

In endothelial cells, USP40 depletion exacerbated experimental lung injury, while its overexpression protected against endotoxin-induced lung injury. USP40 acts on heat shock protein 90β (HSP90β) for its deubiquitination and inactivation, preserving endothelial integrity [5].

In conclusion, Usp40 plays essential roles in maintaining glomerular integrity, regulating podocyte hypertrophy, and is involved in the progression of HCC and endothelial cell function. The use of KO mouse models and knockdown experiments in zebrafish and cell lines has provided insights into its functions in these disease-related processes, highlighting its potential as a therapeutic target in diseases such as FSGS and HCC [1-5].

References:

1. Takahashi, Shohei, Fukuhara, Daisuke, Kimura, Toru, Huber, Otmar, Yan, Kunimasa. 2022. USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage. In Biochemical and biophysical research communications, 614, 198-206. doi:10.1016/j.bbrc.2022.05.043. https://pubmed.ncbi.nlm.nih.gov/35605301/

2. Mo, Huanye, Li, Runtian, Yang, Nan, Xu, Qiuran, Tu, Kangsheng. 2024. USP40 promotes hepatocellular carcinoma progression through a YAP/USP40 positive feedback loop. In Cancer letters, 589, 216832. doi:10.1016/j.canlet.2024.216832. https://pubmed.ncbi.nlm.nih.gov/38537774/

3. Wu, Qingsong, Qiu, Yuanyuan, Guo, Jinhui, Tu, Kangsheng, Hu, Xiaoge. 2024. USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1. In Biology direct, 19, 13. doi:10.1186/s13062-024-00456-3. https://pubmed.ncbi.nlm.nih.gov/38308285/

4. Takagi, Hisashi, Nishibori, Yukino, Katayama, Kan, Takematsu, Hiromu, Yan, Kunimasa. 2017. USP40 gene knockdown disrupts glomerular permeability in zebrafish. In American journal of physiology. Renal physiology, 312, F702-F715. doi:10.1152/ajprenal.00197.2016. https://pubmed.ncbi.nlm.nih.gov/28148530/

5. Miao, Jiaxing, Li, Lian, Shaheen, Nargis, Zhao, Yutong, Zhao, Jing. 2024. The deubiquitinase USP40 preserves endothelial integrity by targeting the heat shock protein HSP90β. In Experimental & molecular medicine, 56, 395-407. doi:10.1038/s12276-024-01160-y. https://pubmed.ncbi.nlm.nih.gov/38307937/