Frommelt Fabian, Ladurner Rene, Goldmann Ulrich, Wolf Gernot, Ingles-Prieto Alvaro, Lineiro-Retes Eva, Gelová Zuzana, Hopp Ann-Katrin, Christodoulaki Eirini, Teoh Shao Thing, Leippe Philipp, Santini Brianda L, Rebsamen Manuele, Lindinger Sabrina, Serrano Iciar, Onstein Svenja, Klimek Christoph, Barbosa Barbara, Pantielieieva Anastasiia, Dvorak Vojtech, Hannich Thomas J, Schoenbett Julian, Sansig Gilles, Mocking Tamara A M, Ooms Jasper F, IJzerman Adriaan P, Heitman Laura H, Sykacek Peter, Reinhardt Juergen, Müller André C, Wiedmer Tabea, Superti-Furga Giulio
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
Novartis Pharma AG, Novartis Biomedical Research NBR/DSc, CH-4002, Basel, Switzerland.
Mol Syst Biol. 2025 May 12. doi: 10.1038/s44320-025-00109-1.
Solute carrier (SLC) transporters form a protein superfamily that enables transmembrane transport of diverse substrates including nutrients, ions and drugs. There are about 450 different SLCs, residing in a variety of subcellular membranes. Loss-of-function of an unusually high proportion of SLC transporters is genetically associated with a plethora of human diseases, making SLCs a rapidly emerging but challenging drug target class. Knowledge of their protein environment may elucidate the molecular basis for their functional integration with metabolic and cellular pathways and help conceive pharmacological interventions based on modulating proteostatic regulation. We aimed at obtaining a global survey of the SLC-protein interaction landscape and mapped the protein-protein interactions of 396 SLCs by interaction proteomics. We employed a functional assessment based on RNA interference of interactors in combination with measurement of protein stability and localization. As an example, we detail the role of a SLC16A6 phospho-degron and the contributions of PDZ-domain proteins LIN7C and MPP1 to the trafficking of SLC43A2. Overall, our work offers a resource for SLC-protein interactions for the scientific community.
溶质载体（SLC）转运蛋白构成一个蛋白质超家族，能够介导包括营养物质、离子和药物在内的多种底物的跨膜转运。大约有450种不同的SLC，存在于各种亚细胞膜中。异常高比例的SLC转运蛋白功能丧失在遗传上与众多人类疾病相关，这使得SLC成为一个迅速兴起但具有挑战性的药物靶点类别。了解它们的蛋白质环境可能会阐明其与代谢和细胞途径功能整合的分子基础，并有助于构思基于调节蛋白质稳态调控的药理学干预措施。我们旨在对SLC - 蛋白质相互作用格局进行全面调查，并通过相互作用蛋白质组学绘制396种SLC的蛋白质 - 蛋白质相互作用图谱。我们采用了基于相互作用分子RNA干扰的功能评估，并结合蛋白质稳定性和定位的测量。例如，我们详细阐述了SLC16A6磷酸化降解子的作用以及PDZ结构域蛋白LIN7C和MPP1对SLC43A2转运的贡献。总体而言，我们的工作为科学界提供了一份SLC - 蛋白质相互作用的资源。
