RNF216 affects the stability of STAU2 in the hypothalamus.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease characterized by gonadal failure due to deficiency in gonadotropin-releasing hormone (GnRH) synthesis, secretion, or action. RNF216 variants have been recently identified in patients with IHH. Ring finger protein 216 (RNF216), as a ubiquitin E3 ligase, catalyzes the ubiquitination of target proteins with high specificity, which consequently modulates the stability, localization, and interaction of the target protein. In this study, we found that RNF216 interacted with Staufen2 (STAU2) and affected the stability of STAU2 through the ubiquitin-proteasome pathway. STAU2, as a double-stranded RNA-binding protein enriched in the nervous system, plays a role in RNA transport, RNA stability, translation, anchoring, and synaptic plasticity. Further, we revealed that STAU2 levels in the hypothalamus of RNF216-/- mice were increased compared with wild-type (WT) mice. The change in STAU2 protein homeostasis may affect a series of RNA cargoes. Therefore, we analyzed the changes in RNA levels in the hypothalamus of RNF216-/- mice and WT mice by RNA sequencing. We found that deletion of RNF216 led to decreased activities of the prolactin signaling pathway, neuroactive ligand-receptor interaction, GnRH signaling pathway, and ovarian steroidogenesis. The weakening of these signal pathways is likely to affect the secretion of GnRH, thereby affecting the development of gonads. Therefore, our study suggests that STAU2 may be a potential therapeutic target for IHH. Further experiments are needed to demonstrate the association between the weakening of these signaling pathways and the RNA-binding protein STAU2.