Znrf1, an E3 ubiquitin ligase, plays crucial roles in multiple biological processes. It is involved in ubiquitination pathways, which are essential for the regulation of protein stability and degradation. This in turn impacts various cellular functions and biological pathways. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying Znrf1's functions [1-10].

In neurons, Znrf1 is constitutively expressed in the central and peripheral nervous systems. In mature neurons, it is activated by stress, degrading AKT to activate GSK3B, thus promoting neuronal/axonal degeneration and Wallerian degeneration [1,9]. In the epidermal growth factor receptor (EGFR) signaling pathway, Znrf1 mediates EGFR ubiquitination, controlling its lysosomal trafficking and degradation. Deletion of Znrf1 leads to delayed receptor degradation and prolonged downstream signaling, increasing susceptibility to herpes simplex virus 1 infection [2]. In kidney tumor cells, Znrf1, through the ZNRF1-mediated ubiquitin proteosome pathway, is involved in destabilizing AKT to inhibit cell growth, as indicated by studies in cell lines and patient-derived xenograft (PDX) model systems [3]. In the context of TLR3-driven immune response, Znrf1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Znrf1-deficient mice have enhanced type I interferon production, yet exacerbated lung barrier damage [4]. Additionally, Znrf1 is involved in endothelial function in diabetes through the ubiquitination of Cav-1 [5], autophagy regulation in Drosophila [6], gemcitabine resistance in pancreatic cancer [7], cell morphogenesis via interaction with tubulin [8], and modulation of inflammation by regulating Cav-1 ubiquitination and degradation [10].

In conclusion, Znrf1 is a key E3 ubiquitin ligase involved in numerous biological functions, including neuronal and axonal degeneration, receptor signaling, tumor cell growth regulation, immune response modulation, endothelial function, autophagy, and cell morphogenesis. Studies using KO or CKO mouse models and other functional studies have revealed its importance in diseases such as neurodegenerative disorders, viral infections, kidney tumors, and diabetes-related vascular complications, providing insights into potential therapeutic strategies [1-10].

References:

1. Araki, Toshiyuki, Wakatsuki, Shuji. 2018. Regulation of neuronal/axonal degeneration by ZNRF1 ubiquitin ligase. In Neuroscience research, 139, 21-25. doi:10.1016/j.neures.2018.07.008. https://pubmed.ncbi.nlm.nih.gov/30118738/

2. Shen, Chia-Hsing, Chou, Chih-Chang, Lai, Ting-Yu, Lee, Chih-Yuan, Hsu, Li-Chung. 2021. ZNRF1 Mediates Epidermal Growth Factor Receptor Ubiquitination to Control Receptor Lysosomal Trafficking and Degradation. In Frontiers in cell and developmental biology, 9, 642625. doi:10.3389/fcell.2021.642625. https://pubmed.ncbi.nlm.nih.gov/33996800/

3. Lu, Jun, Fu, Liang-Min, Cao, Yun, Liu, Zhi-Ping, Luo, Jun-Hang. 2023. LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway. In Oncogene, 42, 1543-1557. doi:10.1038/s41388-023-02666-x. https://pubmed.ncbi.nlm.nih.gov/36966254/

4. Lin, You-Sheng, Chang, Yung-Chi, Chao, Tai-Ling, Lee, Chih-Yuan, Hsu, Li-Chung. 2023. The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage. In The Journal of experimental medicine, 220, . doi:10.1084/jem.20220727. https://pubmed.ncbi.nlm.nih.gov/37158982/

5. Sun, Hai-Jian, Ni, Zhang-Rong, Liu, Yao, Zhu, Xue-Xue, Lu, Qing-Bo. 2024. Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice. In Cardiovascular diabetology, 23, 138. doi:10.1186/s12933-024-02239-6. https://pubmed.ncbi.nlm.nih.gov/38664801/

6. Nicolson, Shannon, Manning, Jantina A, Lim, Yoon, Kumar, Sharad, Denton, Donna. 2024. The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy. In Communications biology, 7, 183. doi:10.1038/s42003-024-05834-1. https://pubmed.ncbi.nlm.nih.gov/38360932/

7. Hu, Chonghui, Xia, Renpeng, Zhang, Xiang, Zheng, Shangyou, Chen, Rufu. 2022. circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis. In Molecular cancer, 21, 24. doi:10.1186/s12943-022-01501-3. https://pubmed.ncbi.nlm.nih.gov/35045883/

8. Yoshida, Koichi, Watanabe, Masashi, Hatakeyama, Shigetsugu. 2009. ZNRF1 interacts with tubulin and regulates cell morphogenesis. In Biochemical and biophysical research communications, 389, 506-11. doi:10.1016/j.bbrc.2009.09.011. https://pubmed.ncbi.nlm.nih.gov/19737534/

9. Wakatsuki, Shuji, Saitoh, Fuminori, Araki, Toshiyuki. 2011. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. In Nature cell biology, 13, 1415-23. doi:10.1038/ncb2373. https://pubmed.ncbi.nlm.nih.gov/22057101/

10. Lee, Chih-Yuan, Lai, Ting-Yu, Tsai, Meng-Kun, Lawrence, Toby, Hsu, Li-Chung. 2017. The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. In Nature communications, 8, 15502. doi:10.1038/ncomms15502. https://pubmed.ncbi.nlm.nih.gov/28593998/