Trim8, a member of the TRIM family proteins, is an E3 ubiquitin ligase. It plays a dual role as both tumor suppressor and oncogene, functioning at the crosstalk of cancer and innate immunity [3]. Trim8 is involved in multiple cellular signaling pathways such as the p53 tumor suppressor, NF-κB, and JAK-STAT pathways, and is associated with various biological processes like cell survival, carcinogenesis, autophagy, apoptosis, differentiation, and inflammation [3,4,5,6,8].

In non-alcoholic fatty liver disease (NAFLD), TRIM8 forms an E3 ligase complex with TRIB3, which catalyzes K48-linked polyubiquitination of HNF4α on lysine 470, leading to HNF4α degradation and NAFLD progression. Abrogating this degradation attenuated the effect of TRIB3 on a diet-induced NAFLD model [1]. In Ewing sarcoma, TRIM8 ubiquitinates and degrades EWS/FLI, a driver fusion-TF. TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated by the cells [2]. In adipocyte inflammation and insulin resistance, inhibiting TRIM8 alleviates these conditions by regulating the DUSP14/MAPKs pathway [7].

In summary, Trim8 is a crucial molecule involved in multiple biological processes and diseases. Through gene knockout (KO) and conditional knockout (CKO) mouse models and other in vivo studies, Trim8 has been shown to play important roles in NAFLD, Ewing sarcoma, and adipocyte-related metabolic disorders, highlighting its potential as a therapeutic target for these diseases.

References:

1. Xiao, Meng-Chao, Jiang, Nan, Chen, Li-Lin, Qian, Hui, Xie, Wei-Fen. 2024. TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability. In Journal of hepatology, 80, 778-791. doi:10.1016/j.jhep.2023.12.029. https://pubmed.ncbi.nlm.nih.gov/38237865/

2. Seong, Bo Kyung A, Dharia, Neekesh V, Lin, Shan, Fischer, Eric S, Stegmaier, Kimberly. 2021. TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma. In Cancer cell, 39, 1262-1278.e7. doi:10.1016/j.ccell.2021.07.003. https://pubmed.ncbi.nlm.nih.gov/34329586/

3. Bhaduri, Utsa, Merla, Giuseppe. 2020. Rise of TRIM8: A Molecule of Duality. In Molecular therapy. Nucleic acids, 22, 434-444. doi:10.1016/j.omtn.2020.08.034. https://pubmed.ncbi.nlm.nih.gov/33230447/

4. Esposito, Jessica Elisabetta, De Iuliis, Vincenzo, Avolio, Francesco, Martinotti, Stefano, Toniato, Elena. 2022. Dissecting the Functional Role of the TRIM8 Protein on Cancer Pathogenesis. In Cancers, 14, . doi:10.3390/cancers14092309. https://pubmed.ncbi.nlm.nih.gov/35565438/

5. Hosseinalizadeh, Hamed, Mohamadzadeh, Omid, Kahrizi, Mohammad Saeed, Klionsky, Daniel J, Mirzei, Hamed. 2023. TRIM8: a double-edged sword in glioblastoma with the power to heal or hurt. In Cellular & molecular biology letters, 28, 6. doi:10.1186/s11658-023-00418-z. https://pubmed.ncbi.nlm.nih.gov/36690946/

6. Marzano, Flaviana, Guerrini, Luisa, Pesole, Graziano, Sbisà, Elisabetta, Tullo, Apollonia. 2021. Emerging Roles of TRIM8 in Health and Disease. In Cells, 10, . doi:10.3390/cells10030561. https://pubmed.ncbi.nlm.nih.gov/33807506/

7. Zhu, Mingxue, Pu, Junliang, Zhang, Ting, Su, Rui, Tang, Chengyong. 2024. Inhibiting TRIM8 alleviates adipocyte inflammation and insulin resistance by regulating the DUSP14/MAPKs pathway. In Adipocyte, 13, 2381262. doi:10.1080/21623945.2024.2381262. https://pubmed.ncbi.nlm.nih.gov/39039652/

8. Caratozzolo, Mariano Francesco, Marzano, Flaviana, Mastropasqua, Francesca, Sbisà, Elisabetta, Tullo, Apollonia. 2017. TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role. In Genes, 8, . doi:10.3390/genes8120354. https://pubmed.ncbi.nlm.nih.gov/29182544/