Usp24-KO Mouse

Usp24, a ubiquitin-specific protease, is involved in multiple biological processes. It plays a role in the ubiquitination-related post-translational modification, which is crucial for maintaining cell homeostasis. Ubiquitination can regulate protein degradation, localization, and activity, and Usp24, as a deubiquitinase, can reverse this process, thus influencing various signaling pathways [1,3,4].

In different disease models, Usp24 shows distinct effects. In a high-fat diet and streptozotocin-induced mouse model of diabetic cardiomyopathy (DCM), increased Usp24 expression was observed. Knockdown of Usp24 in H9c2 cells led to a reduction of NF-κB levels, decreased ferroptosis markers like FACL4, increased antioxidant-related proteins SLC7A11 and FTH1, and improved cell viability, indicating that Usp24 upregulates NF-κB to promote ferroptosis in DCM [1]. In gefitinib-induced drug-resistant mice with doxycycline-induced EGFRL858R lung cancer, targeting Usp24 by the inhibitor USP24-i-101 inhibited drug resistance and activated autophagy, and this effect was abolished after autophagy inhibition, suggesting that targeting Usp24-mediated autophagy induction is required for inhibiting drug resistance [2]. In hepatocellular carcinoma (HCC), knocking down Usp24 promoted HCC proliferation and migration, while overexpression inhibited HCC in vitro and in vivo. Usp24 was found to interact with Beclin1, reducing its K48-linked ubiquitination and promoting autophagy-dependent ferroptosis, and increasing the susceptibility of HCC to sorafenib [3]. In HCC, Usp24 was also upregulated, promoting HCC proliferation and progression by binding to and stabilizing TRAF2, activating the AKT/NF-κB signaling pathway. Deletion of Usp24 enhanced the tumor-killing ability of CD8+ T cells and the efficacy of HCC immunotherapy [4]. In a murine model of neuroblastoma, deletion of Usp24 led to degradation of CRMP2, increased spindle defects, chromosome missegregation, and aneuploidy, suggesting that Usp24 is a tumor suppressor in neuroblastoma [5].

In conclusion, Usp24 is a key regulator in multiple biological processes and diseases. Gene-knockout or inhibitor-based functional studies in mouse models have revealed its roles in promoting ferroptosis in DCM, drug resistance in cancer, and tumorigenesis in HCC, while acting as a tumor suppressor in neuroblastoma. These findings provide important insights into the mechanisms of these diseases and potential therapeutic targets related to Usp24.

References:

1. Wu, Shenglin, Zhou, Yueran, Liang, Jiaquan, Tan, Xuerui, Zhu, Jinxiu. 2023. Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy. In Free radical biology & medicine, 210, 352-366. doi:10.1016/j.freeradbiomed.2023.11.032. https://pubmed.ncbi.nlm.nih.gov/38056575/

2. Young, Ming-Jer, Wang, Shao-An, Chen, Yung-Ching, Lin, Shih-Min, Hung, Jan-Jong. 2024. USP24-i-101 targeting of USP24 activates autophagy to inhibit drug resistance acquired during cancer therapy. In Cell death and differentiation, 31, 574-591. doi:10.1038/s41418-024-01277-7. https://pubmed.ncbi.nlm.nih.gov/38491202/

3. Cao, Jiahui, Wu, Shitao, Zhao, Senfeng, Wang, Weijie, Sun, Yuling. 2024. USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1. In Communications biology, 7, 1279. doi:10.1038/s42003-024-06999-5. https://pubmed.ncbi.nlm.nih.gov/39379617/

4. Zhou, Nana, Guo, Chaoqin, Li, Xiangyu, Xu, Qiuran, Zheng, Xiaoliang. 2024. USP24 promotes hepatocellular carcinoma tumorigenesis through deubiquitinating and stabilizing TRAF2. In Biochemical pharmacology, 229, 116473. doi:10.1016/j.bcp.2024.116473. https://pubmed.ncbi.nlm.nih.gov/39127151/

5. Bedekovics, Tibor, Hussain, Sajjad, Zhang, Ying, Jeon, Young J, Galardy, Paul J. 2020. USP24 Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma. In Cancer research, 81, 1321-1331. doi:10.1158/0008-5472.CAN-20-1777. https://pubmed.ncbi.nlm.nih.gov/33355202/