Senp1, also known as Sentrin/SUMO-specific protease 1, is a cysteine protease that plays crucial roles in multiple biological processes. It processes precursor SUMO proteins into mature forms and deSUMOylates target proteins, thereby participating in various signaling pathways. It is involved in maintaining genomic stability, cell metabolism, and inflammatory responses, which are vital for normal cellular functions and organismal health. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Senp1's functions.

In hepatocyte-specific Senp1-knockout mice, spontaneous NASH-related phenotypes develop in a RIPK1 kinase-dependent manner, indicating Senp1 is a key endogenous inhibitor of RIPK1 in non-alcoholic steatohepatitis (NASH) [1]. In T-cell memory development, SENP1-Sirt3 signalling promotes T-cell survival and memory development, with glucose limitation activating this pathway [2]. In acute kidney injury (AKI) models, activation of the AMPK-coupled SENP1-Sirt3 axis protects against AKI, kidney inflammation, and fibrosis [3]. In cardiomyocyte-specific Senp1-knockout and overexpression mice, Senp1 deletion leads to increased cardiac fibrosis, while overexpression ameliorates adverse ventricular remodeling after myocardial infarction [4]. Also, in a mouse model of transverse aortic constriction, cardiac-specific Senp1 knockdown exacerbates cardiac hypertrophy, while overexpression attenuates it by inhibiting STAT3 signaling [5].

In summary, Senp1 is essential for maintaining normal physiological functions in various tissues. Studies using KO/CKO mouse models have revealed its critical roles in diseases like NASH, T-cell-related immunological processes, AKI, myocardial infarction-induced ventricular remodeling, and pressure-overload-induced cardiac hypertrophy. These findings provide important insights into the pathogenesis of these diseases and suggest Senp1 as a potential therapeutic target.

References:

1. Yan, Lingjie, Zhang, Tao, Wang, Kai, Gu, Jinyang, Xu, Daichao. 2022. SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation. In Nature communications, 13, 7153. doi:10.1038/s41467-022-34993-0. https://pubmed.ncbi.nlm.nih.gov/36414671/

2. He, Jianli, Shangguan, Xun, Zhou, Wei, Wang, Tianshi, Cheng, Jinke. 2021. Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development. In Nature communications, 12, 4371. doi:10.1038/s41467-021-24619-2. https://pubmed.ncbi.nlm.nih.gov/34272364/

3. Zhu, Minyan, He, Jianli, Xu, Yao, Wang, Tianshi, Mou, Shan. 2023. AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 3052-3066. doi:10.1016/j.ymthe.2023.08.014. https://pubmed.ncbi.nlm.nih.gov/37608549/

4. Liu, Zhihao, Bian, Xiyun, Li, Lan, Liu, Xiaozhi, Fan, Guanwei. 2024. SENP1-Mediated HSP90ab1 DeSUMOylation in Cardiomyocytes Prevents Myocardial Fibrosis by Paracrine Signaling. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400741. doi:10.1002/advs.202400741. https://pubmed.ncbi.nlm.nih.gov/38992961/

5. Yang, Dan, Fan, Di, Guo, Zhen, Yang, Zheng, Tang, Qi-Zhu. 2022. SENP1 Protects Against Pressure Overload-Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling. In Journal of the American Heart Association, 11, e027004. doi:10.1161/JAHA.122.027004. https://pubmed.ncbi.nlm.nih.gov/36370010/