Rnf149-KO Mouse

Rnf149, or ring finger protein 149, is an E3 ubiquitin ligase. E3 ubiquitin ligases play a crucial role in the ubiquitination process, which tags proteins for degradation or modulates their function, thus being involved in various cellular pathways and biological processes [1-9].

In a murine myocardial infarction (MI) model, knockout of Rnf149, transplantation of Rnf149 -/- bone marrow, and bone marrow macrophage-specific Rnf149-knockdown exacerbated cardiac dysfunction. Conversely, overexpression of Rnf149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. Rnf149 in infiltrated macrophages restricts inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1, creating a feedback control mechanism to fine-tune macrophage-driven inflammation [1]. In esophageal squamous cell carcinoma (ESCC), inhibition of Rnf149 reversed cisplatin resistance both in vitro and in vivo. Mechanistically, Rnf149 interacts with PHLPP2 and induces its E3 ligase-dependent protein degradation, activating the PI3K/AKT signalling pathway [2]. In acute myeloid leukaemia (AML), Rnf149 accelerates AML progression, modifies the immune milieu, triggers CD8+T cell dysfunction, and influences the transformation of CD8+ Navie.T cells to CD8+TExh, leading to diminished responsiveness to chemotherapeutic agents. Experiments in vivo and in vitro showed Rnf149 enhances AML drug-resistant cell line proliferation and inhibits apoptosis, fostering resistance to Ara-C [3].

In conclusion, Rnf149, as an E3 ubiquitin ligase, is involved in multiple disease-related biological processes. Through gene knockout and other functional studies in mouse models, its roles in cardiac repair post-MI, cancer progression, and drug resistance in ESCC and AML have been revealed. These findings highlight its potential as a therapeutic target in these disease areas.

References:

1. Huang, Chun-Kai, Chen, Zhiyong, Zhou, Zhongxing, Yan, Xiaoxiang, Chai, Dajun. 2024. RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair. In Circulation research, 135, 518-536. doi:10.1161/CIRCRESAHA.123.324023. https://pubmed.ncbi.nlm.nih.gov/38989590/

2. Zhu, Jinrong, Tang, Jiuren, Wu, Yongqi, Jin, Xin, Zhang, Rongxin. 2023. RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling. In Medical oncology (Northwood, London, England), 40, 290. doi:10.1007/s12032-023-02137-z. https://pubmed.ncbi.nlm.nih.gov/37658961/

3. Wu, Xin, Wu, Zhongguang, Deng, Woding, Sun, Xiaoying, Zhao, Qiangqiang. 2023. Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis. In Journal of translational medicine, 21, 760. doi:10.1186/s12967-023-04579-5. https://pubmed.ncbi.nlm.nih.gov/37891580/