ユビキチンリガーゼRNF183は高浸透圧環境下でNKCC1のライソゾームにおける分解を促進する

抄録

We previously reported that RNF183, a member of the RING finger (RNF) ubiquitin ligase family, is specifically expressed in the renal collecting duct and is induced under hypertonic conditions. However, its functional role under such conditions remains unclear. In this study, we used the BirA proximity-biotinylation technique to identify candidate substrates of RNF183; these included the basolateral Na-K-Cl cotransporter (NKCC1). We confirmed that RNF183 interacted with NKCC1 and ubiquitinated NKCC1 through K63-linked ubiquitination, which regulates protein transport. Bafilomycin A1, which inhibits lysosomal function, treatment of RNF183-expressing cells induced ubiquitinated NKCC1 accumulation, suggesting that NKCC1 are degraded in lysosomes by RNF183-mediated ubiquitination. In addition, RNF183 promoted the translocation of NKCC1 from the plasma membrane to intracellular region, compared to treatment with mock control or an RNF183 mutant. Furthermore, this translocation was facilitated under hypertonic conditions. Thus, RNF183 may play an important role in the adaptation to continuous hypertonic conditions through the downregulation of osmoregulatory transporters.