Usp20, or ubiquitin-specific peptidase 20, is a deubiquitylase enzyme. It plays a crucial role in regulating protein stability by removing ubiquitin chains from target proteins. This function is involved in multiple biological pathways, such as cholesterol biosynthesis, reticulophagy, and innate immune signaling, highlighting its overall biological importance. Genetic models, like knockout (KO) mouse models, have been instrumental in studying Usp20's functions [1,2,3,4].

In cholesterol biosynthesis, feeding-induced insulin and glucose increase stimulates mTORC1 to phosphorylate Usp20, which then stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway. Mice with liver-specific Usp20 deletion or USP20(S132A/S134A) knock-in show abolished HMGCR stabilization upon feeding [1]. In reticulophagy, under starvation conditions, Usp20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B, promoting reticulophagy. Genetic deletion of Usp20 in mice leads to accelerated HSV-1-induced degradation of MITA, impairing innate immune signaling [2,4]. Also, USP20-KO mice subjected to transverse aortic constriction show severe systolic function deterioration, eccentric cardiac remodeling, and increased mortality, indicating its role in cardiac homeostasis [3].

In conclusion, Usp20 is essential for maintaining protein stability in various biological processes. Model-based research, especially using Usp20 KO mouse models, has revealed its significance in diseases related to cholesterol metabolism, endoplasmic reticulum homeostasis, innate immunity, and cardiac function. These findings provide potential therapeutic targets for metabolic diseases, viral infections, and heart failure [1,2,3,4].

References:

1. Lu, Xiao-Yi, Shi, Xiong-Jie, Hu, Ao, Qi, Wei, Song, Bao-Liang. 2020. Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. In Nature, 588, 479-484. doi:10.1038/s41586-020-2928-y. https://pubmed.ncbi.nlm.nih.gov/33177714/

2. Zhang, Man, Wang, Zhangshun, Zhao, Qing, Zhang, Zai-Rong, Liu, Yanfen. 2024. USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B to drive reticulophagy. In Autophagy, 20, 1780-1797. doi:10.1080/15548627.2024.2347103. https://pubmed.ncbi.nlm.nih.gov/38705724/

3. Jean-Charles, Pierre-Yves, Roy, Bipradas, Yu, Samuel Mon-Wei, Rockman, Howard A, Shenoy, Sudha K. 2024. USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality. In American journal of physiology. Heart and circulatory physiology, 327, H1257-H1271. doi:10.1152/ajpheart.00329.2024. https://pubmed.ncbi.nlm.nih.gov/39365672/

4. Zhang, Meng-Xin, Cai, Zeng, Zhang, Man, Zhong, Bo, Lin, Dandan. 2019. USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA. In Journal of immunology (Baltimore, Md. : 1950), 202, 2397-2406. doi:10.4049/jimmunol.1801447. https://pubmed.ncbi.nlm.nih.gov/30814308/