Motor Neural Circuit Laboratory • Hirata Group

Voltage-gated sodium channels (Na_V) are known to form clusters at the membranes of excitable cells; however, what governs their transport is largely unknown. We found that the endoplasmic reticulum (ER) and cis-Golgi associated ubiquitin ligase really interesting new gene (RING) finger protein 121 (RNF121) mediates the degradation and membrane localization of Na_V. This apparent quality control of Na_V ensures the transport of properly folded channels to the membranes of excitable cells. To our knowledge, this is the first pathologically relevant identification of a voltage-gated ion channel as a substrate for ER-associated protein degradation, whose degradation is governed by an ER- and Golgi-associated E3-ubiquitin ligase.

A wild-type neuron wherein RNF121 mediates ubiquitination of misfolded Na_V channels marking them for proteasome-mediated degradation. Properly folded Na_V channels (green) associate with Na_Vβ subunits (magenta) in the Golgi apparatus and are transported to the axon initial segment. Of note, some Na_Vβ subunits are transported to the membrane independent of Na_V channels. An RNF121-deficient neuron wherein misfolded Na_V channels (red) accumulates in the ER and cis-Golgi compartments, which, over time, depletes Na_Vβ subunits, preventing them from forming complexes with properly folded Na_V channels, causing an impairment of Na_V transport.