Usp19, or ubiquitin-specific protease 19, is a deubiquitinase enzyme with crucial roles in multiple biological processes. It is involved in pathways such as autophagy, innate immune response, and various cellular regulatory mechanisms, and is of great biological importance in inflammation, cell polarization, and disease development [1-10]. Genetic models, like gene knockout (KO) mouse models, have been instrumental in studying its functions.

In Usp19 -/- mice, there was decreased M2-like macrophage polarization and increased interleukin-1β secretion in response to alum and chitin injections, suggesting its role in anti-inflammatory response and macrophage polarization [1]. Macrophage-specific Usp19 knockout in mice led to attenuated vesicular stomatitis virus (VSV) replication and resistance to VSV infection, uncovering its role in the innate immune response through regulating TBK1 degradation [2]. In hepatocellular carcinoma, knockdown of Usp19 decreased the expression of YAP protein and its target genes, and its upregulation in tissues was associated with poor prognosis [3]. In colorectal carcinogenesis, the USP19-ME1 axis was found to be vital, and in pancreatic cancer, forced expression of Usp19 diminished tumorigenicity [4,5]. Also, inactivation of Usp19 in mice expressing the A53T mutation of α-synuclein led to decreased accumulation of phospho-synuclein positive aggregates and less microglia activation [6]. Th17-lineage-specific Usp19 knockout could potentially help in understanding its role in suppressing Th17-driven pathogenesis in autoimmunity [7].

In conclusion, model-based research, especially using KO mouse models, has revealed that Usp19 plays essential roles in inflammation, immune response, and cancer development. Its functions in macrophage polarization, pathogen response, and tumor-related processes make it a potential therapeutic target for inflammatory diseases, infectious diseases, and various cancers.

References:

1. Liu, Tao, Wang, Liqiu, Liang, Puping, Huang, Junjiu, Cui, Jun. 2020. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. In Cellular & molecular immunology, 18, 2431-2442. doi:10.1038/s41423-020-00567-7. https://pubmed.ncbi.nlm.nih.gov/33097834/

2. Zhao, Xibao, Di, Qianqian, Yu, Juan, Ling, Jing, Chen, Weilin. 2021. USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy. In Autophagy, 18, 891-908. doi:10.1080/15548627.2021.1963155. https://pubmed.ncbi.nlm.nih.gov/34436957/

3. Tian, Zelin, Xu, Chen, He, Weixiang, Zhang, Xuan, Dou, Kefeng. 2023. The deubiquitinating enzyme USP19 facilitates hepatocellular carcinoma progression through stabilizing YAP. In Cancer letters, 577, 216439. doi:10.1016/j.canlet.2023.216439. https://pubmed.ncbi.nlm.nih.gov/37832781/

4. Zhu, Yahui, Gu, Li, Lin, Xi, Prochownik, Edward V, Li, Youjun. . USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1. In Cell reports, 37, 110174. doi:10.1016/j.celrep.2021.110174. https://pubmed.ncbi.nlm.nih.gov/34965422/

5. Wang, Guangfu, Dai, Shangnan, Chen, Jin, Miao, Yi, Lu, Zipeng. 2024. USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer. In Cell death and differentiation, 32, 702-713. doi:10.1038/s41418-024-01426-y. https://pubmed.ncbi.nlm.nih.gov/39627360/

6. Schorova, Lenka, Bedard, Nathalie, Khayachi, Anouar, Durcan, Thomas M, Wing, Simon S. 2023. USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice. In NPJ Parkinson's disease, 9, 157. doi:10.1038/s41531-023-00601-1. https://pubmed.ncbi.nlm.nih.gov/38017009/

7. Zhang, Jing, Bouch, Ronald J, Blekhman, Maxim G, He, Zhiheng. 2021. USP19 Suppresses Th17-Driven Pathogenesis in Autoimmunity. In Journal of immunology (Baltimore, Md. : 1950), 207, 23-33. doi:10.4049/jimmunol.2100205. https://pubmed.ncbi.nlm.nih.gov/34135062/