Deciphering cellular logistics

An unprecedented international effort to decode how cells manage the transport of chemical substances has culminated in four groundbreaking studies published in Molecular Systems Biology. Led by Giulio Superti-Furga at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, and supported by an international consortium of academic and pharmaceutical partners under the European Union's Innovative Medicines Initiative, this decade-long project provides the first comprehensive functional blueprint of chemical transport pathways in human cells.

(Vienna, 19.05.2025) All life depends on the ability of cells to exchange substances with their environment. Nutrients, ions, and vitamins must be absorbed, while waste and special metabolites must be expelled. This fundamental process relies on transporter proteins embedded in cell membranes. Despite their crucial role, the function of many of the hundreds of human transporter-encoding genes has remained a mystery, slowing progress in fields ranging from cancer therapy to metabolic and neurological disease research.

Recognizing this challenge, the Superti-Furga group at CeMM first called for intensified research in a landmark 2015 article in Cell. Ten years later, CeMM and an international consortium have succeeded: by focusing on the largest family of transporters — the solute carriers (SLCs) — they have more than doubled existing knowledge and laid the foundations for future breakthroughs in understanding and targeting these critical proteins.

A Megaproject on Membrane Transporters

In a massive, coordinated effort, 120 researchers from 13 institutions across eight countries came together under the RESOLUTE consortium. After more than five years of laboratory work, most of the experimental data were gathered. The CeMM team, supported by a few key partners and primarily financed by the Austrian Academy of Sciences, then spent an additional year harmonizing, integrating, and interpreting the extensive datasets.

The result is a transformative expansion of the known biology of SLC transporters, integrating multidisciplinary experimental and computational approaches. Their findings illuminate the intricate logistics of chemical traffic within human cells, offering powerful new resources for the scientific and medical communities worldwide.

"It is difficult to find in history a comparably ample and strong ‘push’ of enabling knowledge and tools towards an individual target class, so heavily involved in human disease," says Giulio Superti-Furga, Scientific Director of CeMM and Coordinator of the RESOLUTE consortium. "With these four studies, we hope to have lowered the barrier for transporter research and catalyzed a surge in biomedical discovery for years to come."

The effort not only generated vast scientific insights but also produced an impressive arsenal of reagents, datasets, and analytical tools — all made freely available to the global scientific community via https://re-solute.eu.

"What is the most important outcome is that we were able to annotate most, if not all, solute carriers with functional information and have created a vast arsenal of tools that now serve the global research community. This achievement, culminating in the RESOLUTE knowledge base, represents a unique resource and a true community treasure," says Ulrich Goldmann, a key researcher responsible for data integration.

Giulio Superti-Furga adds: "We are deeply grateful for the support of the Innovative Health Initiative, IHI, (previously Innovative Medicines Initiative, IMI), a partnership of the European Federation of Pharmaceutical Industries and Associations, EFPIA, and the European Union, EU, and the contributions of all our outstanding partners—without whom this project would never have come to life. Since a couple of years, CeMM has shouldered much of the responsibility to validate, annotate, maintain and further develop this invaluable platform. Looking ahead, there is a genuine opportunity for funding bodies and industry stakeholders to help secure the long-term sustainability and expansion of this effort. It is not too late to propose and contribute the means to ensure this community treasure continues to grow and inspire biomedical research worldwide."

Project Manager Tabea Wiedmer, who took over after the premature and tragic death of Daniel Lackner, emphasizes the collaborative spirit of the initiative: "Coordinating the research efforts of such a large group of scientists was a formidable challenge, especially during COVID. We had to develop all sorts of creative strategies to keep partners focused and motivated — but it worked wonderfully. The success relies heavily on efficiently combining expertise across fields."

Key Highlights of the Four Landmark Studies:

• Metabolic Mapping of the SLC Superfamily:
  Hundreds of SLC genes were systematically knocked out or overexpressed in human cell lines, revealing distinct metabolic and gene expression signatures and identifying potential substrates for 71 previously uncharacterized transporters. SLC45A4 was identified as a novel polyamine transporter, opening doors to new metabolic roles. Clustering analysis revealed functional subgroups of SLCs, including those involved in osmolyte balance and glycosylation — functions previously unlinked to specific SLCs.
   
• The Complete SLC Interactome:
  Researchers mapped protein-protein interactions for nearly 400 SLCs, uncovering thousands of new connections and shedding light on fundamental regulatory mechanisms. Specific examples, like the role of PDZ-domain proteins in trafficking, or degrons in stability, illustrate how SLCs are regulated post-translationally.
   
• The First Genetic Interaction Map of SLCs:
  Through more than 35,000 double-knockout experiments, the team identified synthetic lethal interactions and functional redundancies, suggesting new therapeutic targets, particularly among mitochondrial SLCs.  SLC39A1, a zinc transporter, plays an unexpected role in metabolic rewiring and anti-apoptotic signaling in cancer.
   
• An Integrative Functional Landscape of SLCs:
  By combining RESOLUTE-generated data with public datasets, researchers created a richly annotated and freely accessible database, systematically charting the biochemical and biological properties of the SLC transporter family. The work may serve as a blueprint for the systematic extraction and integration of knowledge from high-dimensional, multi-omics data.

Unlocking New Therapeutic Opportunities

SLC transporters are implicated in a wide range of diseases, including cancer, neurological disorders, diabetes, and inherited metabolic conditions. Furthermore, the efficacy of numerous drugs depends on their ability to traverse cellular membranes via specific transporters.

By dramatically expanding the knowledge on transporters and providing essential tools, RESOLUTE paves the way for accelerated therapeutic innovation and new precision medicine approaches.

Resources for the Scientific Community

All reagents, tools, and datasets developed through the RESOLUTE project are openly available at https://re-solute.eu, promoting open science and facilitating research efforts worldwide.

Funding Acknowledgment

This major initiative was funded by the Innovative Medicines Initiative 2 Joint Undertaking under the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Additional support was provided by the Austrian Academy of Sciences and participating institutions.

Project at a Glance 

• Researchers involved: 120 

• Institutions: 13 

• Countries represented: 8 

• Duration: 3 years preliminary work, 5 years of experiments within IMI consortium, 2 years of data integration 

• Studies published: 4 landmark studies and 33 additional publications 

• Cellular molecular transporters investigated: 447 human Solute Carriers (SLCs) 

• Transporter-specific cell line models established: 1,976 

• Assays developed: 119 assays validated for 74 SLCs 

• Protein-binders developed: 30 

• Double-knockout experiments performed: 35,421 

• Protein-protein interactions discovered: 19,991 

• Transporters profiled: gene expression profiles for 441 SLCs, metabolic profiles for 378 SLCs 

• Transported substrates annotated: 2,044 substrates for 329 SLCs 

Pictures attached:

• Photo: The authors of the studies (first row (fltr): Giulio Superti-Furga, Tabea Wiedmer, Ulrich Goldmann; second row (fltr): Gernot Wolf, Fabian Frommelt, Rene Ladurner; third row (fltr): Philipp Leippe, Shao Thing Teoh) © Andreas Angermayr / CeMM
• Graphic: Schematic representation of SLC membrane transporters © Bojan Vilagos

Additional Information:

The study “Metabolic mapping of the human solute carrier superfamily” was published online in Molecular Systems Biology on May 12, 2025. DOI: 10.1038/s44320-025-00106-4

Authors: Tabea Wiedmer, Shao Thing Teoh, Eirini Christodoulaki, Gernot Wolf, Chengzhe Tian, Vitaly Sedlyarov, Abigail Jarret, Philipp Leippe, Fabian Frommelt, Alvaro Ingles-Prieto, Sabrina Lindinger, Barbara M. G. Barbosa, Svenja Onstein, Christoph Klimek, Julio Garcia, Iciar Serrano, Daniela Reil, Diana Santacruz, Mary Piotrowski, Stephen Noell, Christoph Bueschl, Huanyu Li, Gamma Chi, Stefan Mereiter, Tiago Oliveira, Josef M. Penninger, David B. Sauer, Claire M. Steppan, Coralie Viollet, Kristaps Klavins, J. Thomas Hannich, Ulrich Goldmann, Giulio Superti-Furga

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The study “The solute carrier superfamily interactome” was published online in Molecular Systems Biology on May 12, 2025. DOI: 10.1038/s44320-025-00109-1

Authors: Fabian Frommelt, Rene Ladurner, Ulrich Goldmann, Gernot Wolf, Alvaro Ingles-Prieto, Eva Lineiro-Retes, Zuzana Gelová, Ann-Katrin Hopp, Eirini Christodoulaki, Shao Thing Teoh, Philipp Leippe, Brianda L. Santini, Manuele Rebsamen, Sabrina Lindinger, Iciar Serrano, Svenja Onstein, Christoph Klimek, Barbara Barbosa, Anastasiia Pantielieieva, Vojtech Dvorak, J. Thomas Hannich, Julian Schoenbett, Gilles Sansig, Tamara A.M. Mocking, Jasper F. Ooms, Adriaan P. IJzerman, Laura H. Heitman, Peter Sykacek, Juergen Reinhardt, André C Müller, Tabea Wiedmer, Giulio Superti-Furga

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The study “The genetic interaction map of the human solute carrier superfamily” was published online in Molecular Systems Biology on May 12, 2025. DOI: 10.1038/s44320-025-00105-5

Authors: Gernot Wolf, Philipp Leippe, Svenja Onstein, Ulrich Goldmann, Fabian Frommelt, Shao Thing Teoh, Enrico Girardi, Tabea Wiedmer, Giulio Superti-Furga

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The study “Data- and knowledge-derived functional landscape of human solute carriers” was published online in Molecular Systems Biology on May 12, 2025. DOI: 10.1038/s44320-025-00108-2

Authors: Ulrich Goldmann, Tabea Wiedmer, Andrea Garofoli, Vitaly Sedlyarov, Manuel Bichler, Ben Haladik, Gernot Wolf, Eirini Christodoulaki, Alvaro Ingles-Prieto, Evandro Ferrada, Fabian Frommelt, Shao Thing Teoh, Philipp Leippe, Gabriel Onea, Martin Pfeifer, Mariah Kohlbrenner, Lena Chang, Paul Selzer, Jürgen Reinhardt, Daniela Digles, Gerhard F. Ecker, Tanja Osthushenrich, Aidan MacNamara, Anders Malarstig, David Hepworth, Giulio Superti-Furga

The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent and interdisciplinary research institution for molecular medicine under the scientific direction of Giulio Superti-Furga. CeMM is oriented towards medical needs and integrates basic research and clinical expertise to develop innovative diagnostic and therapeutic approaches for precision medicine. Research focuses on cancer, inflammation, metabolic and immune disorders, rare diseases and aging. The Institute's research building is located on the campus of the Medical University and the Vienna General Hospital.

www.cemm.at

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CeMM
Research Center for Molecular Medicine
of the Austrian Academy of Sciences
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www.cemm.at