TRIB3, also known as tribbles pseudokinase 3, is a stress protein that has been implicated in multiple biological processes and diseases. It functions as an endoplasmic reticulum (ER) stress sensor and is involved in pathways such as the regulation of protein stability, immune response modulation, autophagy, and cancer-related signaling pathways [1,2,3]. Its role in these processes makes it of great biological importance, and genetic models, like KO/CKO mouse models, have been crucial in studying its functions.

In NAFLD, TRIB3 forms a complex with TRIM8 to mediate the degradation of HNF4α, promoting disease progression. Inhibiting the TRIB3-HNF4α interaction ameliorates NAFLD in mouse models [1]. In colorectal cancer, Trib3 ablation increases T cell recruitment and sensitizes tumors to immune checkpoint blockade therapy by reducing CD8+ T cell exclusion [2]. In hepatic fibrosis, silencing Trib3 protects against experimentally induced fibrosis, restoring autophagy activity [3]. In head and neck squamous cell carcinoma, TRIB3 silencing promotes ferroptosis-induced cell death [4]. In breast cancer, disturbing the TRIB3-AKT interaction suppresses cancer stem cells in mouse models [5]. In NSCLC, disrupting the TRIB3-EGFR interaction attenuates cancer progression [6]. In colorectal cancer, knockdown of TRIB3 decreases colon neoplasia in mice [7]. In renal cell carcinoma, knocking down TRIB3 reduces lipid accumulation and induces ER-stress-related apoptosis [8]. In high-risk rhabdomyosarcoma, inducible silencing of TRIB3 significantly delays tumor growth and improves survival in vivo [9].

In conclusion, TRIB3 is involved in diverse biological functions such as protein degradation regulation, immune response, autophagy, and cancer-related processes. KO/CKO mouse models have been instrumental in revealing its role in diseases including NAFLD, various cancers, and hepatic fibrosis, providing insights into potential therapeutic strategies for these conditions.

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. Shang, Shuang, Yang, Yu-Wei, Chen, Fei, Zhang, Hai-Zeng, Hua, Fang. 2022. TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. In Science translational medicine, 14, eabf0992. doi:10.1126/scitranslmed.abf0992. https://pubmed.ncbi.nlm.nih.gov/34985967/

3. Zhang, Xiao-Wei, Zhou, Ji-Chao, Peng, Dian, Huang, Bo, Hu, Zhuo-Wei. 2019. Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. In Autophagy, 16, 782-796. doi:10.1080/15548627.2019.1635383. https://pubmed.ncbi.nlm.nih.gov/31286822/

4. Chen, Li, Lin, Wanzun, Zhang, Haojiong, Lu, Jiade J, Kong, Lin. 2024. TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis. In Cell death & disease, 15, 178. doi:10.1038/s41419-024-06472-5. https://pubmed.ncbi.nlm.nih.gov/38429254/

5. Yu, Jin-Mei, Sun, Wei, Wang, Zhen-He, Cui, Bing, Hu, Zhuo-Wei. 2019. TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. In Nature communications, 10, 5720. doi:10.1038/s41467-019-13700-6. https://pubmed.ncbi.nlm.nih.gov/31844113/

6. Yu, Jiao-Jiao, Zhou, Dan-Dan, Yang, Xiao-Xiao, Hua, Fang, Hu, Zhuo-Wei. 2020. TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target. In Nature communications, 11, 3660. doi:10.1038/s41467-020-17385-0. https://pubmed.ncbi.nlm.nih.gov/32694521/

7. Hua, Fang, Shang, Shuang, Yang, Yu-Wei, Huang, Bo, Hu, Zhuo-Wei. 2018. TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis. In Gastroenterology, 156, 708-721.e15. doi:10.1053/j.gastro.2018.10.031. https://pubmed.ncbi.nlm.nih.gov/30365932/

8. Li, Jun, Zhang, Qian, Guan, Yupeng, Chen, Xianju, Pang, Jun. 2024. TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2. In Cell death & disease, 15, 240. doi:10.1038/s41419-024-06627-4. https://pubmed.ncbi.nlm.nih.gov/38561354/

9. Gallo-Oller, Gabriel, Pons, Guillem, Sansa-Girona, Júlia, Gallego, Soledad, Roma, Josep. 2024. TRIB3 silencing promotes the downregulation of Akt pathway and PAX3-FOXO1 in high-risk rhabdomyosarcoma. In Experimental hematology & oncology, 13, 38. doi:10.1186/s40164-024-00503-9. https://pubmed.ncbi.nlm.nih.gov/38581035/