TRIM21, also known as Ro52, is a RING finger domain-containing ubiquitin E3 ligase. It plays crucial roles in multiple immunological processes such as antibody-dependent intracellular neutralization, antiviral response, and protein ubiquitination. It is also involved in pathways like the cGAS/STING cytosolic DNA sensing pathway, and is associated with various biological functions including stress granule homeostasis, redox regulation, and is linked to diseases such as cancer, autoimmune diseases, and neurodegenerative diseases [5,2,6]. Genetic models are valuable for studying TRIM21's functions.

In cancer, depending on the cancer type and carcinogenesis effector, TRIM21 may enhance cancer proliferation or increase the ubiquitination of cancer-triggering proteins leading to their degradation, suggesting its potential as a cancer therapeutic target [1]. In nasopharyngeal carcinoma, knockout of TRIM21 potentiates the antigen-presenting capacity of cancer cells and activates cytotoxic T-cell-mediated antitumour immunity by modulating the cGAS/STING pathway, and high TRIM21 expression is associated with poor prognosis after radiotherapy [3]. In obesity-induced inflammation, targeting macrophage TRIM21 with antisense oligonucleotide-loaded vesicles effectively inhibits inflammation and related metabolic disorders, as UBE2M-mediated neddylation of TRIM21 regulates obesity-related inflammation [4]. In acute kidney injury, loss of TRIM21 in mice alleviates ferroptosis induced by ischemia/reperfusion, suggesting it as a potential target for AKI treatment [7]. In influenza A virus infection, TRIM21 in mammals acts as a host restriction factor, inhibiting the replication of certain IAV subtypes by degrading M1 protein, and drives host-adaptive mutations of the virus [8].

In conclusion, TRIM21 is a multifunctional E3 ubiquitin ligase. Model-based research, especially gene knockout in mouse models, has revealed its roles in cancer, autoimmune and metabolic diseases, acute kidney injury, and antiviral defense. These findings contribute to understanding disease mechanisms and potentially developing new therapeutic strategies for these disease areas.

References:

1. Alomari, Munther. 2021. TRIM21 - A potential novel therapeutic target in cancer. In Pharmacological research, 165, 105443. doi:10.1016/j.phrs.2021.105443. https://pubmed.ncbi.nlm.nih.gov/33508433/

2. Yang, Cuiwei, Wang, Zhangshun, Kang, Yingjin, Bai, Yun, Liu, Yanfen. 2023. Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. In Autophagy, 19, 1934-1951. doi:10.1080/15548627.2022.2164427. https://pubmed.ncbi.nlm.nih.gov/36692217/

3. Li, Jun-Yan, Zhao, Yin, Gong, Sha, Ma, Jun, Liu, Na. 2023. TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models. In Nature communications, 14, 865. doi:10.1038/s41467-023-36523-y. https://pubmed.ncbi.nlm.nih.gov/36797289/

4. Lu, Xinliang, Kong, Xianghui, Wu, Hao, Wang, Jianli, Cai, Zhijian. 2023. UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders. In Cell metabolism, 35, 1390-1405.e8. doi:10.1016/j.cmet.2023.05.011. https://pubmed.ncbi.nlm.nih.gov/37343564/

5. Holwek, Emilia, Opinc-Rosiak, Aleksandra, Sarnik, Joanna, Makowska, Joanna. 2023. Ro52/TRIM21 - From host defense to autoimmunity. In Cellular immunology, 393-394, 104776. doi:10.1016/j.cellimm.2023.104776. https://pubmed.ncbi.nlm.nih.gov/37857191/

6. Pan, Ji-An, Sun, Yu, Jiang, Ya-Ping, Lin, Richard Z, Zong, Wei-Xing. . TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. In Molecular cell, 61, 720-733. doi:10.1016/j.molcel.2016.02.007. https://pubmed.ncbi.nlm.nih.gov/26942676/

7. Sun, Xiaolin, Huang, Ning, Li, Peng, Gao, Shenglan, Xin, Hong. 2023. TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. In Life sciences, 321, 121608. doi:10.1016/j.lfs.2023.121608. https://pubmed.ncbi.nlm.nih.gov/36958437/

8. Lin, Lulu, Wang, Xingbo, Chen, Zhen, Huang, Yu, Zhou, Jiyong. 2023. TRIM21 restricts influenza A virus replication by ubiquitination-dependent degradation of M1. In PLoS pathogens, 19, e1011472. doi:10.1371/journal.ppat.1011472. https://pubmed.ncbi.nlm.nih.gov/37343022/