The inositol pyrophosphate 5-InsP7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

Alfred C Chin; Zhe Gao; Andrew M Riley; David Furkert; Christopher Wittwer; Amit Dutta; Tomas Rojas; Evan R Semenza; Robin A Felder; Jennifer L Pluznick; Henning J Jessen; Dorothea Fiedler; Barry V L Potter; Solomon H Snyder; Chenglai Fu

doi:10.1126/sciadv.abb8542

The inositol pyrophosphate 5-InsP₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

Sci Adv. 2020 Oct 28;6(44):eabb8542. doi: 10.1126/sciadv.abb8542. Print 2020 Oct.

Authors

Alfred C Chin¹, Zhe Gao^{2

3}, Andrew M Riley⁴, David Furkert⁵, Christopher Wittwer⁶, Amit Dutta⁶, Tomas Rojas¹, Evan R Semenza¹, Robin A Felder⁷, Jennifer L Pluznick⁸, Henning J Jessen⁶, Dorothea Fiedler⁵, Barry V L Potter⁴, Solomon H Snyder^{9

10

11}, Chenglai Fu^{12

3}

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
³ Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.
⁴ Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Oxford, UK.
⁵ Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
⁶ Institute of Organic Chemistry and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
⁷ Department of Pathology, University of Virginia, Charlottesville, VA, USA.
⁸ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ssnyder@jhmi.edu chenglaifu@tmu.edu.cn.
¹⁰ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China. ssnyder@jhmi.edu chenglaifu@tmu.edu.cn.

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-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.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

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