RNF10 role in protein homeostasis in synaptic plasticity

RNF10 is a mulLfuncLonal protein with emerging roles in proteostasis, translaLon control, and neuronal plasLcity. RNF10 has been characterized as an E3 ubiquiLn ligase involved in iniLal ribosome quality control (iRQC), where it promotes ubiquiLnaLon of defecLve 40S ribosomal subunits during translaLon iniLaLon, parLcularly under condiLons of ribosomal imbalance or amino acid starvaLon. Through this acLvity, RNF10 contributes to the clearance of stalled ribosomes and maintenance of translaLonal homeostasis. In neurons, RNF10 addiLonally funcLons 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 synapLc acLvity, coupling synapLc signaling to transcripLonal programs. RNF10 is essenLal for long-term potenLaLon–dependent modulaLon of dendriLc spine morphology and for shaping dendriLc architecture in hippocampal neurons. To invesLgate the role of RNF10 in neuronal protein translaLon, we analyzed RNF10 silenced primary hippocampal neurons exposed to synapLc sLmulaLon. Transcriptomic profiling by RNA sequencing revealed broad alteraLons in gene expression programs associated with translaLon, stress responses, and proteostasis. In parallel, SUnSET assays demonstrated that RNF10 downregulaLon impairs early translaLon control, while ubiquiLnaLon and proteasome acLvity assays revealed altered ribosome-associated ubiquiLnaLon and increased proteolyLc acLvity. Together, these findings idenLfy RNF10 as a key regulator of neuronal translaLon by integraLng synapLc signaling, ribosome quality control, and stress-responsive translaLonal pathways.