Usp38, an ubiquitin-specific protease, plays diverse roles in biological processes. It is involved in pathways such as the regulation of protein ubiquitination and deubiquitination, which are crucial for maintaining normal cellular functions. Usp38's functions are significant in inflammation, fibrosis, cell proliferation, and viral infection responses, highlighting its overall biological importance. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying Usp38's functions [1-10].

In KO/CKO mouse models, Usp38 deficiency promotes IL-33–induced downstream proinflammatory responses, making Usp38−/− mice more susceptible to inflammatory damage, death, and pulmonary fibrosis [1]. In the context of myocardial infarction, cardiac-conditional USP38 knockout (USP38-CKO) reduces inflammatory markers and factors, alleviating cardiac fibrosis, electrical remodeling, and susceptibility to ventricular arrhythmias (VAs), while USP38 overexpression exacerbates these effects [2,3]. In pressure-overload-induced heart failure, USP38 knockout decreases the susceptibility of VAs by modulating ion channel and Cx43 expression and inhibiting TBK1/AKT/CAMKII signaling, while overexpression has the opposite effect [4]. In atrial fibrillation studies, USP38-CKO attenuates atrial inflammation, fibrosis, and AF susceptibility after myocardial infarction or pressure overload, as it inhibits the activation of the TAK1/NF-κB signaling pathway, while overexpression over-activates this pathway [3,5].

In conclusion, Usp38 is a key regulator in multiple biological processes. Model-based research, particularly using KO/CKO mouse models, has revealed its role in diseases such as pulmonary fibrosis, cardiac remodeling, arrhythmias, and atrial fibrillation. Understanding Usp38's functions provides potential therapeutic targets for these disease areas.

References:

1. Yi, Xue-Mei, Li, Mi, Chen, Yun-Da, Shu, Hong-Bing, Li, Shu. 2022. Reciprocal regulation of IL-33 receptor-mediated inflammatory response and pulmonary fibrosis by TRAF6 and USP38. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2116279119. doi:10.1073/pnas.2116279119. https://pubmed.ncbi.nlm.nih.gov/35238669/

2. Gong, Yang, Kong, Bin, Shuai, Wei, Zhang, Jing Jing, Huang, He. . USP38 regulates inflammatory cardiac remodeling after myocardial infarction. In Clinical science (London, England : 1979), 137, 1665-1681. doi:10.1042/CS20230728. https://pubmed.ncbi.nlm.nih.gov/37903290/

3. Gong, Yang, Yu, Tingting, Shuai, Wei, Zhang, Jingjing, Huang, He. 2023. USP38 exacerbates atrial inflammation, fibrosis, and susceptibility to atrial fibrillation after myocardial infarction in mice. In Molecular medicine (Cambridge, Mass.), 29, 157. doi:10.1186/s10020-023-00750-2. https://pubmed.ncbi.nlm.nih.gov/37953295/

4. Pan, Yucheng, Xiao, Zheng, Yang, Hongjie, Shuai, Wei, Huang, He. 2024. USP38 exacerbates pressure overload-induced left ventricular electrical remodeling. In Molecular medicine (Cambridge, Mass.), 30, 97. doi:10.1186/s10020-024-00846-3. https://pubmed.ncbi.nlm.nih.gov/38937697/

5. Xiao, Zheng, Pan, Yucheng, Kong, Bin, Shuai, Wei, Huang, He. . Ubiquitin-specific protease 38 promotes inflammatory atrial fibrillation induced by pressure overload. In Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 26, . doi:10.1093/europace/euad366. https://pubmed.ncbi.nlm.nih.gov/38288617/