TRIM15, a member of the tripartite motif protein family, functions as an E3 ubiquitin ligase. It is involved in multiple cellular processes, regulating various signaling pathways such as ERK, AKT/FOXO1, Keap1-Nrf2, and NF-κB [1,3,4,8]. It also plays a role in cell migration by regulating focal adhesion disassembly [7]. These functions are crucial for normal cellular activities and are implicated in numerous biological processes and disease conditions.

In disease-related studies, TRIM15 has been shown to promote the progression of melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) [1,2,3,4]. For example, knockdown of TRIM15 inhibits the growth of drug-responsive and drug-resistant melanomas [1]. In pancreatic cancer, its overexpression promotes cancer progression by upregulating toll-like receptor 4 [2]. In NSCLC, it facilitates cancer cell proliferation and metastasis by targeting Keap1 for ubiquitination and degradation, leading to Nrf2 stabilization [3]. In HCC, it contributes to tyrosine kinase inhibitor (TKI) resistance [4]. In osteoarthritis, conditional deletion of Trim15 in mouse chondrocytes impairs skeletal growth and affects OA phenotypes, indicating its role in chondrocyte senescence and OA progression [5]. Also, knockdown of TRIM15 inhibits the activation of hepatic stellate cells, suggesting its involvement in liver fibrosis [6]. In contrast, in gastric adenocarcinoma, high expression of TRIM15 in normal tissues compared to tumors and its inhibitory effect on tumor cell invasion imply its anti-tumor role [9].

In conclusion, TRIM15 is a multifunctional E3 ubiquitin ligase involved in various biological processes and disease conditions. Studies using gene knockout or conditional knockout mouse models have significantly contributed to understanding its role in cancer, osteoarthritis, and liver fibrosis. These findings suggest that TRIM15 could be a potential therapeutic target for these diseases.

References:

1. Zhu, Guixin, Herlyn, Meenhard, Yang, Xiaolu. 2021. TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. In Nature cell biology, 23, 978-991. doi:10.1038/s41556-021-00732-8. https://pubmed.ncbi.nlm.nih.gov/34497368/

2. Cai, Hongkun, Zhao, Jingyuan, Zhang, Qiyue, Wu, Heshui, Ren, Dianyun. 2024. Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167183. doi:10.1016/j.bbadis.2024.167183. https://pubmed.ncbi.nlm.nih.gov/38657551/

3. Liang, Manman, Wang, Lijing, Sun, Zhengui, Zhao, Wenying, Geng, Biao. 2022. E3 ligase TRIM15 facilitates non-small cell lung cancer progression through mediating Keap1-Nrf2 signaling pathway. In Cell communication and signaling : CCS, 20, 62. doi:10.1186/s12964-022-00875-7. https://pubmed.ncbi.nlm.nih.gov/35534896/

4. Yang, Chong, Jin, Xin, Liu, Xingchao, Liao, Dongxu, Zhang, Yu. 2023. TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs. In Cell death & disease, 14, 47. doi:10.1038/s41419-023-05577-7. https://pubmed.ncbi.nlm.nih.gov/36670097/

5. Li, Zhuang, Zhang, Weituo, Wei, Xiao Ying, Shen, Shuying, Ji, Ming-Liang. 2025. TRIM15 drives chondrocyte senescence and osteoarthritis progression. In Science translational medicine, 17, eadq1735. doi:10.1126/scitranslmed.adq1735. https://pubmed.ncbi.nlm.nih.gov/40138455/

6. Zhang, Junpei, Chen, Yin, Tian, Yi, Chen, Shiyao, Liu, Hailing. 2021. Knockdown of TRIM15 inhibits the activation of hepatic stellate cells. In Journal of molecular histology, 52, 839-848. doi:10.1007/s10735-021-09997-7. https://pubmed.ncbi.nlm.nih.gov/34142270/

7. Uchil, Pradeep D, Pawliczek, Tobias, Reynolds, Tracy D, Calderwood, David A, Mothes, Walther. 2014. TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly. In Journal of cell science, 127, 3928-42. doi:10.1242/jcs.143537. https://pubmed.ncbi.nlm.nih.gov/25015296/

8. Roy, Milton, Singh, Kritarth, Shinde, Anjali, Currim, Fatema, Singh, Rajesh. 2021. TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-κB pathway by promoting turnover of K63 linked ubiquitination of TAK1. In Cellular signalling, 91, 110210. doi:10.1016/j.cellsig.2021.110210. https://pubmed.ncbi.nlm.nih.gov/34871740/

9. Chen, Weilin, Lu, Chuanhui, Hong, Jianming. 2018. TRIM15 Exerts Anti-Tumor Effects Through Suppressing Cancer Cell Invasion in Gastric Adenocarcinoma. In Medical science monitor : international medical journal of experimental and clinical research, 24, 8033-8041. doi:10.12659/MSM.911142. https://pubmed.ncbi.nlm.nih.gov/30412518/