RNF10 ROLE IN PROTEIN HOMEOSTASIS IN SYNAPTIC PLASTICITY EVENTS

RNF10 is a multifunctional protein with emerging roles in proteostasis, translation control, and neuronal plasticity. RNF10 has been characterized as an E3 ubiquitin ligase involved in initial ribosome quality control (iRQC), where it promotes ubiquitination of defective 40S ribosomal subunits during translation initiation, particularly under conditions of ribosomal imbalance or amino acid starvation. Through this activity, RNF10 contributes to the clearance of stalled ribosomes and maintenance of translational homeostasis. In neurons, RNF10 additionally functions as a synaptonuclear messenger. It binds the C-terminal region of the GluN2A subunit of NMDA receptors (NMDARs) and translocates from synapses to the nucleus in response to synaptic activity, coupling synaptic signaling to transcriptional programs. RNF10 is essential for long-term potentiation dependent modulation of dendritic spine morphology and for shaping dendritic architecture in hippocampal neurons. To investigate the role of RNF10 in neuronal protein translation, we analyzed RNF10 silenced primary hippocampal neurons exposed to synaptic stimulation. Transcriptomic profiling by RNA sequencing revealed broad alterations in gene expression programs associated with translation, stress responses, and proteostasis. In parallel, SUnSET assays demonstrated that RNF10 downregulation impairs early translation control, while ubiquitination and proteasome activity assays revealed altered ribosome-associated ubiquitination and increased proteolytic activity. Together, these findings identify RNF10 as a key regulator of neuronal translation by integrating synaptic signaling, ribosome quality control, and stress-responsive translational pathways.