BDNF exerts an NRF2-dependent cytoprotective function via a receptor-independent pathway
Year: 2025
Type: article
Abstract: The ancestral and ubiquitous KEAP1-NRF2 cellular defense system is controlled by chemical inducers and intracellular proteins. Here, we show that an extracellular protein, BDNF, can directly control this cytoprotective system via a receptor-independent pathway. Thanks to a highly conserved C-terminal CPP sequence, BDNF freely crosses the cell membrane, binds to KEAP1, and thereby promotes the nuclear translocation of NRF2 to exert an effective cytoprotective effect. The high conservation of the CPP sequence over 450 million years demonstrates the essential role of this signaling pathway. The receptor-independent cytoprotective effect, in addition to the canonical receptor-dependent neurotrophic effect, shows that a protein can exert distinct effects via receptor-dependent and receptor-independent mechanisms, as described for small molecules. As extracellular BDNF is present throughout the body, it can control the cellular defenses of cells, including those without receptors. Consequently, any change in BDNF extracellular levels is likely to modify the cytoprotective response and thus contribute to numerous pathologies.
Source: Cell Reports
Authors: Julia Fath, Franck Brouillard, Damien Claverie, Alexandre Cabayé, Philippe Nuss, Serge Chwetzoff, Romain Coppée, Tahar Bouceba, Elodie Bouvier, Victoria Poillerat, Myriam Salameh, Jenny Molet, Aïda Padilla-Ferrer, Marion Russeau, Philippe Couvert, Sabine Lévi, Francine Acher, Marie-Pierre Golinelli-Cohen, Gérard Chassaing, Germain Trugnan, Christophe Bernard, Jean-Jacques Benoliel, Chrystel Becker
Institutions: Inserm, École Pratique des Hautes Études, Université Paris Cité, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris Sciences et Lettres, Université Paris-Saclay, Institut Gustave Roussy, CEA Grenoble, Assistance Publique – Hôpitaux de Paris, Health and Functional Exposomics, Pitié-Salpêtrière Hospital, Laboratoire d'Électronique des Technologies de l'Information, Centre National de la Recherche Scientifique, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, SPPIN - Saints-Pères Paris Institute for Neurosciences, Dassault Systèmes (France), Sorbonne Université, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Virologie et Immunologie Moléculaires, Université de Rouen Normandie, Institut de Biologie Paris-Seine, Intégrité du génome et cancers, Institut de Chimie des Substances Naturelles, Institut du Fer à Moulin, Unité de recherche sur les maladies cardiovasculaires et métaboliques, Fondation pour l’innovation en Cadiométabolisme et Nutrition, École Normale Supérieure - PSL, Laboratoire des Biomolécules, Aix-Marseille Université, Institut de Neurosciences des Systèmes, Observatoire de Physique du Globe de Clermont-Ferrand
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W4416451409