Hypertonicity-induced RNF183 targets NKCC1 to protect kidney collecting duct cells but induces apoptosis in colon cells.

RING-finger protein 183 (RNF183) is a ubiquitin ligase specifically expressed in the kidney and especially in collecting ducts that are constantly exposed to hypertonic stress. The expression of RNF183 in the colon is low but is upregulated in patients with inflammatory bowel disease (IBD) and patients with colorectal cancer. However, the function and relationship of RNF183 with these diseases remain unclear. Here, we identify the Na-K-2Cl co-transporter NKCC1 as a substrate of RNF183. RNF183 promotes K63-linked ubiquitination of NKCC1, leading to its lysosomal degradation, which is enhanced under hypertonic conditions. Dysregulation of RNF183 expression increases hypertonic-induced cell death in Rnf183-knockout mIMCD-3 cells and RNF183-overexpressing Caco-2 cells, accompanied by an increase in cleaved caspase-3. Under isotonic and hypertonic conditions, intracellular Na+ homeostasis is disrupted in these cells. Notably, RNF183 expression exerts opposing effects in mIMCD-3 cells, which endogenously express RNF183, and in Caco-2 cells, which do not. Thus, RNF183, which targets multiple ion transporters, including NKCC1 identified in this study, may play an important role in the adaptation to hypertonic conditions in the kidney, whereas aberrant expression of RNF183 could cause the development of diseases such as IBD and colorectal cancer.