A receptor-independent signaling pathway for BDNF

Fath, J.; Brouillard, F.; Cabaye, A.; Claverie, D.; Nuss, P.; Poillerat, V.; Chwetzoff, S.; Bouceba, T.; Bouvier, E.; Salameh, M.; Molet, J.; Padilla-Ferrer, A.; Couvert, P.; Acher, F.; Golinelli-Cohen, M.-P.; Chassaing, G.; Trugnan, G.; bernard, c.; Benoliel, J.-J.; Becker, C.

doi:10.1101/2022.08.23.504973

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bioRxiv · 10.1101/2022.08.23.504973

A receptor-independent signaling pathway for BDNF

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Abstract

In addition to its well-known receptor-mediated function in cell survival, differentiation and growth, we report that the extracellular brain-derived neurotrophic factor (BDNF) also controls the intracellular KEAP1-NRF2 cytoprotective system by a receptor-independent pathway. Extracellular BDNF can cross the cell membrane as it possesses a protein-translocation domain, also known as cell-penetrating peptide. This membrane crossing process is energy-independent, ruling out endocytosis and receptor-dependent mechanisms. Once in the cytosol, BDNF binds to KEAP1 with a nanomolar affinity, enabling nuclear translocation of NRF2 and transcription of NRF2-target genes. BDNF is thus a major regulator of NRF2 activation. A dysfunction of this BDNF-KEAP1-NRF2 pathway may be involved in most diseases where antioxidant and cytoprotective functions are altered. This novel form of communication, whereby a receptor ligand protein exerts a biological activity by crossing the cell membrane, opens new avenues for cell signaling.

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Fath, J., Brouillard, F., Cabaye, A., Claverie, D., Nuss, P., Poillerat, V., Chwetzoff, S., Bouceba, T., Bouvier, E., Salameh, M., Molet, J., Padilla-Ferrer, A., Couvert, P., Acher, F., Golinelli-Cohen, M.-P., Chassaing, G., Trugnan, G., bernard, c., Benoliel, J.-J., Becker, C.. 2022-08-23. A receptor-independent signaling pathway for BDNF. https://doi.org/10.1101/2022.08.23.504973

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