Trim38-flox Mouse

TRIM38, a member of the tripartite motif (TRIM)-containing protein family, functions as a ubiquitin E3 protein ligase. It is involved in multiple intracellular physiological processes, including innate immune and inflammatory responses, cell proliferation, differentiation, apoptosis, and antiviral defense. It is associated with various signaling pathways such as TRAF6/TAK1/NF-κB, MYC, and RIG-I-mediated IFN-I regulation [1,2,3,4].

In a rat cardiomyoblast cell line (H9c2), TRIM38 knockdown activated the TAK1/NF-κB signaling pathway, reducing anti-apoptotic and anti-inflammatory capacity during hypoxia/reoxygenation (H/R) injury, while overexpression alleviated H/R-induced cell injury [1]. In colorectal cancer, decreased TRIM38, due to DNA hypermethylation of its promoter, was correlated with poor prognosis, and its overexpression inhibited cancer cell proliferation and metastasis by enhancing CCT6A ubiquitination to inhibit the MYC pathway [2]. In respiratory syncytial virus-infected cells, IFN-I promoted TRIM38 expression, which downregulated IFN-I production by competing with TRIM25 to bind RIG-I [3]. In chondrocytes, IL-1β stimulation decreased TRIM38 levels, and overexpression protected chondrocytes from IL-1β-induced apoptosis and degeneration by suppressing NF-κB signaling [5]. In the context of the maternal-fetal interface, TRIM38-mediated K48 ubiquitination of MITA in M2 macrophages inhibited pyroptosis, maintaining the immunosuppressed state [6]. In osteoclast and osteoblast differentiation, TRIM38 overexpression in precursor cells affected differentiation and function by regulating NF-κB activation through TAB2 degradation [7]. In human glioma cells, TRIM38 overexpression restricted Zika virus replication by upregulating the RIG-I/MDA5 pathway and promoting ubiquitin-mediated degradation of the viral NS3 protein [8]. In bladder cancer, low TRIM38 expression was associated with poor prognosis, and it restricted tumor progression by promoting GLUT1 ubiquitination and degradation [9]. In a NAFLD mouse model, TRIM38 depletion deteriorated hepatic steatosis, inflammation, and fibrosis, and TRIM38 overexpression mitigated these effects by promoting TAB2 degradation and inhibiting the MAPK signaling pathway [10].

In conclusion, TRIM38 plays crucial roles in various biological processes and diseases. Through gene-knockout or related loss-of-function models in different cell lines and animal models, it has been revealed that TRIM38 can regulate innate immune and inflammatory responses, cell apoptosis, differentiation, and tumor progression. These findings contribute to understanding the underlying mechanisms of related diseases and suggest TRIM38 as a potential therapeutic target for diseases such as myocardial ischemia/reperfusion injury, colorectal cancer, osteoarthritis, and NAFLD.