Trim8, a member of the TRIM (TRIpartite Motif-containing) family proteins, is an E3 ubiquitin ligase. It plays a central role in the immune response and orchestrates various biological processes such as cell survival, carcinogenesis, autophagy, apoptosis, differentiation, and inflammation [3,4]. Trim8 is involved in multiple signaling pathways, including the p53 tumor suppressor, NF-κB, and JAK-STAT pathways, and its expression can be induced by IFNγ [3,6].

In non-alcoholic fatty liver disease (NAFLD), the TRIB3-Trim8 E3 ligase complex is responsible for the degradation of hepatic nuclear factor 4α (HNF4α). Disrupting the interaction between TRIB3 and Trim8 can stabilize HNF4α protein levels, thus ameliorating NAFLD progression [1]. In Ewing sarcoma, Trim8 acts as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF. Trim8 knockout led to increased EWS/FLI protein levels that were not tolerated by the cells [2]. In adipocyte inflammation and insulin resistance, Trim8 deficiency decreased the level of inflammatory cytokines, increased glucose uptake content, and improved insulin signaling transduction, suggesting that Trim8 can regulate these processes by regulating the MAPKs pathway which is dependent on DUSP14 [5].

In conclusion, Trim8 is a crucial molecule involved in multiple biological processes and diseases. Gene knockout models in mice, such as those in NAFLD, Ewing sarcoma, and adipocyte-related studies, have revealed its role in disease-associated protein regulation, cell survival, and inflammation-related processes. These findings highlight the potential of targeting Trim8-related pathways for the treatment of corresponding 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. 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/

5. 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/

6. 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/