biostudies-literatureChin ACUnited States Public Health ServiceNIDDK NIH HHSNIMH NIH HHSNHLBI NIH HHSNational Natural Science Foundation of ChinaWellcome Trusteabb8542https://www.ebi.ac.uk/biostudies/studies/S-EPMC7608788biostudies-literatureUnknown6(44)Sodium/potassium-transporting adenosine triphosphatase (Na⁺/K⁺-ATPase) is one of the most abundant cell membrane proteins and is essential for eukaryotes. Endogenous negative regulators have long been postulated to play an important role in regulating the activity and stability of Na⁺/K⁺-ATPase, but characterization of these regulators has been elusive. Mechanisms of regulating Na⁺/K⁺-ATPase homeostatic turnover are unknown. Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP₇), generated by inositol hexakisphosphate kinase 1 (IP6K1), promotes physiological endocytosis and downstream degradation of Na⁺/K⁺-ATPase-α1. Deletion of IP6K1 elicits a twofold enrichment of Na⁺/K⁺-ATPase-α1 in plasma membranes of multiple tissues and cell types. Using a suite of synthetic chemical biology tools, we found that 5-InsP₇ binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85α to disinhibit its interaction with Na⁺/K⁺-ATPase-α1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na⁺/K⁺-ATPase-α1. Our study identifies 5-InsP₇ as an endogenous negative regulator of Na⁺/K⁺-ATPase-α1.Science advancesThe inositol pyrophosphate 5-InsP₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α.PMC7608788R01 MH018501R01 DK107726101010R37 MH01850181870232R01 HL128512MH18501101010/B/13/ZFurkert DRiley AMSnyder SHChin ACWittwer CPotter BVLFu CJessen HJDutta APluznick JLFiedler DGao ZFelder RARojas TSemenza ERfalseThe inositol pyrophosphate 5-InsP₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α.Sodium/potassium-transporting adenosine triphosphatase (Na⁺/K⁺-ATPase) is one of the most abundant cell membrane proteins and is essential for eukaryotes. Endogenous negative regulators have long been postulated to play an important role in regulating the activity and stability of Na⁺/K⁺-ATPase, but characterization of these regulators has been elusive. Mechanisms of regulating Na⁺/K⁺-ATPase homeostatic turnover are unknown. Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP₇), generated by inositol hexakisphosphate kinase 1 (IP6K1), promotes physiological endocytosis and downstream degradation of Na⁺/K⁺-ATPase-α1. Deletion of IP6K1 elicits a twofold enrichment of Na⁺/K⁺-ATPase-α1 in plasma membranes of multiple tissues and cell types. Using a suite of synthetic chemical biology tools, we found that 5-InsP₇ binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85α to disinhibit its interaction with Na⁺/K⁺-ATPase-α1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na⁺/K⁺-ATPase-α1. Our study identifies 5-InsP₇ as an endogenous negative regulator of Na⁺/K⁺-ATPase-α1.2020-01-01T00:00:00Z2020 Oct2024-10-14T20:23:33.284Z2020-11-07T10:14:56ZS-EPMC76087883311574010.1126/sciadv.abb8542