RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels

Following their synthesis in the endoplasmic reticulum (ER), voltagegated sodium channels (Na_V) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which Na_V channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis-Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of Na_V channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary Na_Vβ subunits. Collectively, these results indicate that RNF121 participates in the quality control of Na_V channels during their synthesis and subsequent transport to the membrane.