Systematic analyses of lipid mobilization by human lipid transfer proteins

Article Article scientifique Article Systematic analyses of lipid mobilization by human lipid transfer proteins eng 2026-01-07 author Titeca Kevin 0000-0002-7677-8252 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.,European Molecular Biology Laboratory, EMBL, Heidelberg, Germany. 944300 author Chiapparino Antonella European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.,AB Sciex Germany GmbH, <City>, Germany. author Hennrich Marco L 0000-0003-2853-9748 European Molecular Biology Laboratory, EMBL, Heidelberg, Germany. marco.hennrich@abseabio.com.,Absea Biotechnology GmbH Berlin, Berlin, Germany. marco.hennrich@abseabio.com. author Türei Dénes 0000-0002-7249-9379 Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany. author Moqadam Mahmoud 0000-0002-3456-5064 Department of Chemistry, University of Bergen, Bergen, Norway.,Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway. author Talandashti Reza 0000-0003-4087-475X Department of Chemistry, University of Bergen, Bergen, Norway.,Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.,Department of Biochemistry, University of Oxford, Oxford, UK. author Cuveillier Camille 0000-0003-2081-1938 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 417910 Département de physiologie cellulaire et métabolisme (PHYME) author Van Ek Larissa 0000-0002-8047-1560 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 932186 author Zukowska Joanna 0000-0001-8287-7428 European Molecular Biology Laboratory, EMBL, Heidelberg, Germany. author Triana Sergio 0000-0003-0370-7821 European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.,Institute for Medical Engineering and Science (IMES) and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA. author Echelard Florian Department of Chemistry, University of Bergen, Bergen, Norway.,Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway. author Nielsen Inger Ødum Cell Death and Metabolism group, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark. author Foged Mads Møller 0000-0003-2225-6114 Cell Death and Metabolism group, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark. author Gehin Charlotte European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.,École Polytechnique Fédérale de Lausanne (EPFL), <City>, Switzerland. author Olechnovic Kliment Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.,CNRS, Grenoble INP, LJK, Université Grenoble Alpes, Grenoble, France. author Grudinin Sergei 0000-0002-1903-7220 CNRS, Grenoble INP, LJK, Université Grenoble Alpes, Grenoble, France. author Saez-Rodriguez Julio 0000-0002-8552-8976 Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany.,EMBL European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK. author Alexandrov Theodore 0000-0001-9464-6125 European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.,Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.,DeepCyte Inc., San Diego, CA, USA. author Maeda Kenji 0000-0002-9080-5691 Cell Death and Metabolism group, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark. author Reuter Nathalie 0000-0002-3649-7675 Department of Chemistry, University of Bergen, Bergen, Norway.,Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway. author Gavin Perrin Anne-Claude 0000-0003-4917-2340 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. anne-claude.gavin@unige.ch. 23293 Département de physiologie cellulaire et métabolisme (PHYME) 10.1038/s41586-025-10040-y 41501472 0028-0836 https://www.nature.com/articles/s41586-025-10040-y Lipid transfer proteins (LTPs) maintain the specialized lipid compositions of organellar membranes1,2 . In humans, many LTPs are implicated in diseases3 , but for the majority, the cargo and auxiliary lipids facilitating transfer remain unknown. We have combined biochemical, lipidomic and computational methods to systematically characterize LTP-lipid complexes4 and measure how LTP gains of function affect cellular lipidomes. We identified bound lipids for approximately half of the hundred LTPs analyzed, confirming known ligands, while discovering new ones across most LTP families. Gains in LTP function affected the cellular abundance of both their known and newly identified lipid ligands, indicating comparable functional relevance of the two ligand sets. Using structural bioinformatics, we have characterized mechanisms contributing to lipid selectivity, identifying preferences based on head group or acyl chain. We demonstrate some basic principles of how LTPs mobilise their ligands. They commonly interact with several classes of lipids and exhibit broad but selective preference, not only for particular head groups, but also for lipid species with shorter acyl chains containing one or two unsaturations, suggesting that only subsets of lipid species are efficiently mobilized. The datasets represent a resource for further analysis in different cell types and states, such as those associated with pathologies. Membrane Protein structure Lipid metabolism Lipid transport Lipidomics Dewey 612 European Commission The multi-omics role of lipid transfer proteins in lipid metabolism 843407 LipTransProMet EU H2020 Swiss National Science Foundation A new molecular mechanism of APOE lipidation: impact of APOE polymorphism and metabolic stressors 10001127 CH 134 Département de physiologie cellulaire et métabolisme 21C false 1276 Métabolisme des lipides 1001 Nature 88f55e49-5889-468b-a93b-9c8bb3208961 Article (Accepted version) Public s41586-025-10040-y_reference.pdf 28499400 application/pdf Restricted 2026-07-08 781d970319563dbb7154625bca6c3074250965be82e45d5e02b316e9b431df1e openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Systematic analyses of lipid mobilization by human lipid transfer proteins	Nature	2026	64	3
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Titeca, Kevin