Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2

Huanyu Z. Li, Ashley C. W. Pike, Yung-Ning Chang, Dheeraj Prakaash, Zuzana Gelova, Josefina Stanka, Christophe Moreau, Hannah C. Scott, Frank Wunder, Gernot Wolf, Andreea Scacioc, Gavin McKinley, Helena Batoulis, Shubhashish Mukhopadhyay, Andrea Garofoli, Adán Pinto-Fernández, Benedikt M. Kessler, Nicola A. Burgess-Brown, Saša Štefanić, Tabea Wiedmer, Katharina L. Dürr (), Vera Puetter (), Alexander Ehrmann (), Syma Khalid (), Alvaro Ingles-Prieto (), Giulio Superti-Furga () and David B. Sauer ()
Additional contact information
Huanyu Z. Li: University of Oxford
Ashley C. W. Pike: University of Oxford
Yung-Ning Chang: Nuvisan ICB GmbH
Dheeraj Prakaash: University of Oxford
Zuzana Gelova: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Josefina Stanka: Bayer AG
Christophe Moreau: University of Oxford
Hannah C. Scott: University of Oxford
Frank Wunder: Bayer AG
Gernot Wolf: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Andreea Scacioc: University of Oxford
Gavin McKinley: University of Oxford
Helena Batoulis: Bayer AG
Shubhashish Mukhopadhyay: University of Oxford
Andrea Garofoli: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Adán Pinto-Fernández: University of Oxford
Benedikt M. Kessler: University of Oxford
Nicola A. Burgess-Brown: University of Oxford
Saša Štefanić: University of Zurich, AgroVet-Strickhof
Tabea Wiedmer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Katharina L. Dürr: University of Oxford
Vera Puetter: Nuvisan ICB GmbH
Alexander Ehrmann: Bayer AG
Syma Khalid: University of Oxford
Alvaro Ingles-Prieto: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
David B. Sauer: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis. Here, we use a combination of cryo-electron microscopy, immunofluorescence, in vitro binding and in vivo S1P export assays, and molecular dynamics simulations to probe SPNS2’s substrate binding and transport. These results reveal the transporter’s binding mode to its native substrate S1P, the therapeutic FTY720-P, and the reported SPNS2-targeting inhibitor 33p. Further capturing an inward-facing apo state, our structures illuminate the protein’s mechanism for exchange between inward-facing and outward-facing conformations. Finally, using these structural, localization, and S1P transport results, we identify how pathogenic mutations ablate the protein’s export activity and thereby lead to hearing loss.

Date: 2025
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DOI: 10.1038/s41467-025-55942-7

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