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The inositol pyrophosphate 5-InsP 7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Chin Alfred C., Gao Zhe, Riley Andrew M., Furkert David, Wittwer Christopher, Dutta Amit, Rojas Tomas, Semenza Evan R., Felder Robin A., Pluznick Jennifer L., Jessen Henning J., Fiedler Dorothea, Potter Barry V. L., Snyder Solomon H., Fu Chenglai,
Project Discovery and mechanistic dissection of novel signaling pathways controlling phosphate homeostasis in eukaryotes
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Original article (peer-reviewed)

Journal Science Advances
Volume (Issue) 6(44)
Page(s) eabb8542 - eabb8542
Title of proceedings Science Advances
DOI 10.1126/sciadv.abb8542

Open Access

URL http://doi.org/10.1126/sciadv.abb8542
Type of Open Access Publisher (Gold Open Access)

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-InsP 7 ), 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-InsP 7 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-InsP 7 as an endogenous negative regulator of Na + /K + -ATPase-α1.
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