BDNF exerts an NRF2-dependent cytoprotective function via a receptor-independent pathway
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.
Authors
- Francine Acher (ORCID: https://orcid.org/0000-0002-5413-4181)
- Philippe Nuss (ORCID: https://orcid.org/0000-0002-3514-4501)
- Serge Chwetzoff
- Victoria Poillerat (ORCID: https://orcid.org/0009-0000-2542-7199)
- Chrystel Becker (ORCID: https://orcid.org/0000-0002-0680-2851)
- Damien Claverie (ORCID: https://orcid.org/0000-0003-2880-2948)
- Julia Fath (ORCID: https://orcid.org/0000-0001-9594-2647)
- Tahar Bouceba
- Christophe Bernard (ORCID: https://orcid.org/0000-0003-3014-1966)
- Romain Coppée (ORCID: https://orcid.org/0000-0002-3024-5928)
- Franck Brouillard
- Philippe Couvert (ORCID: https://orcid.org/0000-0002-7607-2057)
- Sabine Lévi (ORCID: https://orcid.org/0000-0002-9927-0945)
- Elodie Bouvier
- Jenny Molet (ORCID: https://orcid.org/0000-0001-6997-6712)
- Alexandre Cabayé (ORCID: https://orcid.org/0000-0002-2461-2082)
- Marie‐Pierre Golinelli‐Cohen (ORCID: https://orcid.org/0000-0002-6738-8631)
- Aïda Padilla-Ferrer (ORCID: https://orcid.org/0000-0001-7797-9155)
- Marion Russeau (ORCID: https://orcid.org/0000-0002-9681-0491)
- Germain Trugnan
- Myriam Salameh
- Gérard Chassaing
- Jean‐Jacques Benoliel
Institutions
- Institut polytechnique de Grenoble (FR)
- Délégation Paris 5 (FR)
- Centre National de la Recherche Scientifique (FR)
- Institut de Chimie des Substances Naturelles (FR)
- Inserm (FR)
- École Pratique des Hautes Études (FR)
- Université Sorbonne Nouvelle (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- CEA Grenoble (FR)
- Sorbonne Université (FR)
- Sorbonne Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut de Biologie Paris-Seine (FR)
- Institut de Neurosciences des Systèmes (FR)
- Observatoire de Physique du Globe de Clermont-Ferrand (FR)
- Toxicologie, Pharmacologie et Signalisation Cellulaire (FR)
- Virologie et Immunologie Moléculaires (FR)
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR)
- Pitié-Salpêtrière Hospital (FR)
- Institut de Psychiatrie et Neurosciences de Paris (FR)
- Centre de Recherche Saint-Antoine (FR)
- Institut du Fer à Moulin (FR)
- Unité de recherche sur les maladies cardiovasculaires et métaboliques (FR)
- Laboratoire d'Électronique des Technologies de l'Information (FR)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- Laboratoire des Biomolécules (FR)
- SPPIN - Saints-Pères Paris Institute for Neurosciences (FR)
- Dassault Systèmes (France) (FR)
- Université Paris 1 Panthéon-Sorbonne (FR)
- Université de Rouen Normandie (FR)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1016/j.celrep.2025.116587
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 0.00