PIP2-mediated oligomerization of the endosomal sodium/proton exchanger NHE9

Surabhi Kokane, Ashutosh Gulati, Pascal F. Meier, Rei Matsuoka, Tanadet Pipatpolkai, Giuseppe Albano, Tin Manh Ho, Lucie Delemotte, Daniel Fuster () and David Drew ()
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Surabhi Kokane: Stockholm University
Ashutosh Gulati: Stockholm University
Pascal F. Meier: Stockholm University
Rei Matsuoka: Stockholm University
Tanadet Pipatpolkai: KTH Royal Institute of Technology
Giuseppe Albano: University of Bern
Tin Manh Ho: University of Bern
Lucie Delemotte: KTH Royal Institute of Technology
Daniel Fuster: University of Bern
David Drew: Stockholm University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The strict exchange of Na+ for H+ ions across cell membranes is a reaction carried out in almost every cell. Na+/H+ exchangers that perform this task are physiological homodimers, and whilst the ion transporting domain is highly conserved, their dimerization differs. The Na+/H+ exchanger NhaA from Escherichia coli has a weak dimerization interface mediated by a β-hairpin domain and with dimer retention dependent on cardiolipin. Similarly, organellar Na+/H+ exchangers NHE6, NHE7 and NHE9 also contain β-hairpin domains and recent analysis of Equus caballus NHE9 indicated PIP2 lipids could bind at the dimer interface. However, structural validation of the predicted lipid-mediated oligomerization has been lacking. Here, we report cryo-EM structures of E. coli NhaA and E. caballus NHE9 in complex with cardiolipin and phosphatidylinositol-3,5-bisphosphate PI(3,5)P2 lipids binding at their respective dimer interfaces. We further show how the endosomal specific PI(3,5)P2 lipid stabilizes the NHE9 homodimer and enhances transport activity. Indeed, we show that NHE9 is active in endosomes, but not at the plasma membrane where the PI(3,5)P2 lipid is absent. Thus, specific lipids can regulate Na+/H+ exchange activity by stabilizing dimerization in response to either cell specific cues or upon trafficking to their correct membrane location.

Date: 2025
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DOI: 10.1038/s41467-025-58247-x

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