A first blueprint of chemical transport pathways in human cells

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.