Rnf216, also known as Ring finger protein 216, belongs to the RING family of E3 ubiquitin ligases. As an E3 ubiquitin ligase, it catalyzes the ubiquitination of target proteins, thus modulating their stability, localization, and interaction. It is involved in multiple pathways including the prolactin signaling pathway, neuroactive ligand-receptor interaction, GnRH signaling pathway, and ovarian steroidogenesis, and is of great importance in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis [1,2,3,8]. Mouse models have been crucial in studying its gene function [2,3,8].

Targeted deletion of Rnf216 in mice results in male infertility due to disrupted spermatogenesis, affecting the prophase of meiosis I. Spermatocytes are arrested at the zygotene stage and undergo apoptosis at the pachytene stage. Rnf216 also interacts with PRKACB and promotes its degradation through the ubiquitin-lysosome pathway in the testes [3]. In addition, Rnf216 -/- mice show decreased activities in several signal pathways in the hypothalamus, potentially affecting GnRH secretion and gonad development. Rnf216 is also essential for the migration of GnRH neurons, as its knockdown in GN11 cells inhibits migration through increased Beclin1-mediated autophagy [1,7]. In ducks, duck RNF216 inhibits the duRIG-I signaling pathway and restricts the replication of H5N1 avian influenza virus [4]. In experimental subarachnoid hemorrhage models, upregulation of RNF216 is observed, and its knockdown protects against neuronal injury [5]. In glioblastoma, RNF216 is overexpressed, promotes cell growth, and protects against radiation-induced apoptosis and DNA damage by regulating p53 degradation [6].

In conclusion, Rnf216 plays essential roles in spermatogenesis, male fertility, and the regulation of the HPG axis through its E3 ubiquitin ligase function. Mouse knockout models have revealed its significance in these processes, and its dysregulation is associated with various diseases such as Gordon Holmes syndrome, hypogonadotropic hypogonadism, and some cancers. Understanding Rnf216 provides insights into the mechanisms of these biological processes and diseases.

References:

1. Yang, Han, Zhu, Yong, Li, Xin, Jiang, Zuiming, Dai, Wenting. 2023. RNF216 affects the stability of STAU2 in the hypothalamus. In Development, growth & differentiation, 65, 408-417. doi:10.1111/dgd.12877. https://pubmed.ncbi.nlm.nih.gov/37439148/

2. Melnick, Ashley F, Gao, Yuen, Liu, Jiali, Hess, Rex A, Chen, Chen. . RNF216 is essential for spermatogenesis and male fertility†. In Biology of reproduction, 100, 1132-1134. doi:10.1093/biolre/ioz006. https://pubmed.ncbi.nlm.nih.gov/30649198/

3. Li, Dengfeng, Li, Fangfang, Meng, Lanlan, Tan, Yue-Qiu, Li, Jia-Da. . RNF216 regulates meiosis and PKA stability in the testes. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e21460. doi:10.1096/fj.202002294RR. https://pubmed.ncbi.nlm.nih.gov/33724554/

4. He, Zhuoliang, Li, Weiqiang, Zhang, Meng, Zhao, Luxiang, Jiao, Peirong. . RNF216 Inhibits the Replication of H5N1 Avian Influenza Virus and Regulates the RIG-I Signaling Pathway in Ducks. In Journal of immunology (Baltimore, Md. : 1950), 213, 187-203. doi:10.4049/jimmunol.2300540. https://pubmed.ncbi.nlm.nih.gov/38829131/

5. Chen, Tao, Zhu, Jie, Wang, Yu-Hai. 2020. RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1-AMPAR pathway. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 15080-15092. doi:10.1096/fj.201903151RRRR. https://pubmed.ncbi.nlm.nih.gov/32918771/

6. Xie, Songwang, Hong, Zhen, Li, Yan, Li, Shaoquan, Liu, Yongchang. 2022. RNF216 Alleviates Radiation-Induced Apoptosis and DNA Damage Through Regulating Ubiquitination-Mediated Degradation of p53 in Glioblastoma. In Molecular neurobiology, 59, 4703-4717. doi:10.1007/s12035-022-02868-6. https://pubmed.ncbi.nlm.nih.gov/35594003/

7. Li, Fangfang, Li, Dengfeng, Liu, Huadie, Chen, Dan-Na, Li, Jia-Da. 2019. RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy. In Frontiers in endocrinology, 10, 12. doi:10.3389/fendo.2019.00012. https://pubmed.ncbi.nlm.nih.gov/30733708/

8. George, Arlene J, Dong, Bin, Lail, Hannah, Wanders, Desiree, Mabb, Angela M. 2022. The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis. In iScience, 25, 104386. doi:10.1016/j.isci.2022.104386. https://pubmed.ncbi.nlm.nih.gov/35620441/