@article{fc165bb0cc5145e78febb4c93267da75,
title = "The inositol pyrophosphate 5-InsP7drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α",
abstract = "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-InsP7binds 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-InsP7as an endogenous negative regulator of Na+/K+-ATPase-α1.",
author = "Chin, {Alfred C.} and Zhe Gao and Riley, {Andrew M.} and David Furkert and Christopher Wittwer and Amit Dutta and Tomas Rojas and Semenza, {Evan R.} and Felder, {Robin A.} and Pluznick, {Jennifer L.} and Jessen, {Henning J.} and Dorothea Fiedler and Potter, {Barry V.L.} and Snyder, {Solomon H.} and Chenglai Fu",
note = "Funding Information: This work was supported by a USPHS grant MH18501 (to S.H.S.) and the National Natural Science Foundation of China (81870232 to C.F.). A.C.C. was supported by a Johns Hopkins University Provost's Undergraduate Research Award, Barry M. Goldwater Scholarship, Astronaut Scholarship, R&D Systems Scholarship, and Irene & Eric Simon Brain Research Foundation Summer Fellowship. H.J.J. was supported by the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy (CIBSS-EXC-2189-Project ID 390939984) and by the DFG Grant JE 572/4-1. B.V.L.P. is a Wellcome Trust Senior Investigator (grant 101010). J.L.P. was supported by grants R01DK-107726 and R01HL-128512. Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",
year = "2020",
month = oct,
day = "28",
doi = "10.1126/sciadv.abb8542",
language = "English (US)",
volume = "6",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "44",
}