TRIM40, a tripartite motif-containing protein, functions as an E3 ligase. It is involved in multiple cellular pathways, such as those related to cell-cell junctions, antiviral immune responses, and inflammation regulation [1-10]. Its role in maintaining normal physiological functions and the development of diseases makes it a gene of great biological importance. Genetic models, like knockout (KO) mouse models, have been crucial in understanding its functions.

In inflammatory bowel disease (IBD), TRIM40 is upregulated in a subset of patients. Trim40-deficient male mice are highly resistant to dextran sulfate sodium (DSS)-induced colitis, suggesting that TRIM40 drives IBD by disrupting cortical actin formation and epithelial barrier function [1]. In colorectal cancer, TRIM40 is down-regulated, and its over-expression can inhibit cell proliferation both in vitro and in vivo. It directly binds to and ubiquitinates ROCK1, reducing c-Myc protein stability and leading to G0/G1 phase arrest [2]. In diabetic retinopathy, promoting TRIM40 expression by intravenous injection of AAV-TRIM40 ameliorates DR phenotypes in STZ-treated mice, as it suppresses inflammation via disrupting Reelin/DAB1 signaling [3]. In IgA nephropathy, TRIM40, which is downregulated by IgA1, can inhibit IgA1-induced proliferation of glomerular mesangial cells by inactivating the NLRP3 inflammasome through ubiquitination [4].

In conclusion, TRIM40 plays diverse and significant roles in various biological processes and diseases. KO mouse models have been instrumental in uncovering its functions in IBD, colorectal cancer, diabetic retinopathy, and IgA nephropathy. Understanding TRIM40 provides insights into disease mechanisms and potential therapeutic targets for these diseases.

References:

1. Kang, Sujin, Kim, Jaekyung, Park, Areum, Lee, Sungwook, Park, Boyoun. 2023. TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity. In Nature communications, 14, 700. doi:10.1038/s41467-023-36424-0. https://pubmed.ncbi.nlm.nih.gov/36755029/

2. Hu, Fangyu, Zhao, Lingling, Wang, Junyu, Huang, Chuanshu, Huang, Haishan. 2024. TRIM40 interacts with ROCK1 directly and inhibits colorectal cancer cell proliferation through the c-Myc/p21 axis. In Biochimica et biophysica acta. Molecular cell research, 1871, 119855. doi:10.1016/j.bbamcr.2024.119855. https://pubmed.ncbi.nlm.nih.gov/39357549/

3. Xiaoling, Xu, Xinmei, Lan, Shuhua, Fu, Lin, Xie, Xiong, Yu. 2023. TRIM40 ameliorates diabetic retinopathy through suppressing inflammation via Reelin/DAB1 signaling disruption: A mechanism by proteasomal degradation of DAB1. In Biochemical and biophysical research communications, 664, 117-127. doi:10.1016/j.bbrc.2023.04.020. https://pubmed.ncbi.nlm.nih.gov/37146559/

4. Shen, Jiaojiao, Wu, Qing, Liang, Tingyu, Yuan, Meijie, Shen, Peicheng. 2021. TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination. In Molecular immunology, 140, 225-232. doi:10.1016/j.molimm.2021.10.012. https://pubmed.ncbi.nlm.nih.gov/34763147/