UCHL1, also known as PGP 9.5, is a multifunctional protein belonging to the deubiquitinase family [4]. It is highly expressed in neurons of the brain and spinal cord, playing important roles in regulating cellular free ubiquitin levels, redox state, and degradation of select proteins. It is also involved in various pathways such as the AKT1, HIF-1α, and IGF-1-induced Akt/mTOR/HIF-1α pathways, which are relevant to multiple biological processes and diseases [1,2,3].

In pulmonary arterial hypertension (PAH) models, Uchl1 knockout rats (Uchl1-/-) and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) showed reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling, suggesting UCHL1 deficiency attenuates PAH by reducing AKT1 [1]. In ischemic heart injury, cardiomyocytes derived from UCHL1-/-human induced pluripotent stem cells (hiPSCs) were more susceptible to hypoxia/re-oxygenation induced injury, indicating a protective role of UCHL1 via stabilizing HIF-1α [2]. In triple-negative breast cancer (TNBC), UCHL1 promoted tumorigenesis, cancer stemness, migration, and invasion in vivo and in vitro. Knockdown of UCHL1 sensitized TNBC cells to endocrine therapy [5,6].

In conclusion, UCHL1 has diverse essential biological functions related to protein regulation and redox state. Studies using Uchl1 knockout and conditional knockout mouse models have revealed its roles in neurodegenerative diseases, brain injury, PAH, ischemic heart injury, neuroendocrine carcinomas, and breast cancer, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Tang, Haiyang, Gupta, Akash, Morrisroe, Seth A, Garcia, Joe G N, Desai, Ankit A. 2024. Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension. In Circulation, 150, 302-316. doi:10.1161/CIRCULATIONAHA.123.065304. https://pubmed.ncbi.nlm.nih.gov/38695173/

2. Geng, Bingchuan, Wang, Xiaoliang, Park, Ki Ho, Cai, Chuanxi, Zhu, Hua. 2022. UCHL1 protects against ischemic heart injury via activating HIF-1α signal pathway. In Redox biology, 52, 102295. doi:10.1016/j.redox.2022.102295. https://pubmed.ncbi.nlm.nih.gov/35339825/

3. Guo, Chipeng, Liang, Lizhu, Zheng, Jingbin, Huang, Jingang, Wang, Liangchun. . UCHL1 aggravates skin fibrosis through an IGF-1-induced Akt/mTOR/HIF-1α pathway in keloid. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e23015. doi:10.1096/fj.202300153RR. https://pubmed.ncbi.nlm.nih.gov/37256780/

4. Day, Ian N M, Thompson, Rod J. 2009. UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein. In Progress in neurobiology, 90, 327-62. doi:10.1016/j.pneurobio.2009.10.020. https://pubmed.ncbi.nlm.nih.gov/19879917/

5. Tian, Chuntao, Liu, Ying, Liu, Yixiong, Song, Junyang, Liu, Jin. 2022. UCHL1 promotes cancer stemness in triple-negative breast cancer. In Pathology, research and practice, 240, 154235. doi:10.1016/j.prp.2022.154235. https://pubmed.ncbi.nlm.nih.gov/36434856/

6. Li, Juan, Liang, Yu, Zhou, Shijie, Chen, Jie, Wu, Chihua. 2024. UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5. In Breast cancer research : BCR, 26, 44. doi:10.1186/s13058-024-01800-1. https://pubmed.ncbi.nlm.nih.gov/38468288/