Altas B, Rhee HJ, Ju A, Solís HC, Karaca S, Winchenbach J, Kaplan-Arabaci O, Schwark M, Ambrozkiewicz MC, Lee C, Spieth L, Wieser GL, Chaugule VK, Majoul I, Hassan MA, Goel R, Wojcik SM, Koganezawa N, Hanamura K, Rotin D, Pichler A, Mitkovski M, de Hoz L, Poulopoulos A, Urlaub H, Jahn O, Saher G, Brose N, Rhee J, Kawabe H
Journal of Cell Biology
J Cell Biol. 2024 Jan 1;223(1):e201902050.
Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of the Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.