ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor

Abstract

Mineralocorticoid receptor (MR) signaling regulates both renal Na-Cl reabsorption and K+ excretion. We previously demonstrated that phosphorylation of S843 in the MR ligand-binding domain in renal intercalated cells is involved in the balance of these activities by regulating ligand binding and signaling. However, the kinase that phosphorylates MRS843 is unknown. Using a high-throughput screen assay of 197 kinases, we found that ULK1 is the principal kinase that is responsible for the phosphorylation of MRS843. The results were confirmed by in vitro kinase assay, mass spectrometry, and siRNA knockdown experiments. Notably, phosphorylation at MRS843 was markedly reduced in ULK1/2 double knockout mouse embryonic fibroblasts. Upstream, we show that ULK1 activity is inhibited by phosphorylation induced by angiotensin II via mTOR in cell culture and in vivo. These findings implicate mTOR and ULK1 as regulators of MR activity in intercalated cells, a pathway that is critical for maintaining electrolyte homeostasis. Shibata et al. use a high-throughput screen assay and show that unc-51-like kinase 1 (ULK1) phosphorylates and regulates mineralocorticoid receptor (MR). Upstream, angiotensin II inhibits ULK1 and decreases MR phosphorylation via mTOR. These findings implicate mTOR and ULK1 as regulators of MR in intercalated cells.