Sumoylation regulates FMRP-mediated dendritic spine elimination and maturation

Anouar Khayachi, Carole Gwizdek, Gwénola Poupon, Damien Alcor, Magda Chafai, Frédéric Cassé, Thomas Maurin, Marta Prieto, Alessandra Folci, Fabienne Graeve, Sara Castagnola, Romain Gautier, Lenka Schorova, Céline Loriol, Marie Pronot, Florence Besse, Frédéric Brau, Emmanuel Deval, Barbara Bardoni and Stéphane Martin ()
Additional contact information
Anouar Khayachi: Université Côte d’Azur, CNRS, IPMC
Carole Gwizdek: Université Côte d’Azur, CNRS, IPMC
Gwénola Poupon: Université Côte d’Azur, CNRS, IPMC
Damien Alcor: Université Côte d’Azur, INSERM, C3M
Magda Chafai: Université Côte d’Azur, CNRS, IPMC
Frédéric Cassé: Université Côte d’Azur, CNRS, IPMC
Thomas Maurin: Université Côte d’Azur, CNRS, IPMC
Marta Prieto: Université Côte d’Azur, CNRS, IPMC
Alessandra Folci: Université Côte d’Azur, CNRS, IPMC
Fabienne Graeve: Université Côte d’Azur, CNRS, INSERM, iBV
Sara Castagnola: Université Côte d’Azur, CNRS, IPMC
Romain Gautier: Université Côte d’Azur, CNRS, IPMC
Lenka Schorova: Université Côte d’Azur, CNRS, IPMC
Céline Loriol: Université Côte d’Azur, CNRS, IPMC
Marie Pronot: Université Côte d’Azur, CNRS, IPMC
Florence Besse: Université Côte d’Azur, CNRS, INSERM, iBV
Frédéric Brau: Université Côte d’Azur, CNRS, IPMC
Emmanuel Deval: Université Côte d’Azur, CNRS, IPMC
Barbara Bardoni: Université Côte d’Azur, INSERM, CNRS, IPMC
Stéphane Martin: Université Côte d’Azur, INSERM, CNRS, IPMC

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism. FXS results from the functional absence of the fragile X mental retardation protein (FMRP) leading to abnormal pruning and consequently to synaptic communication defects. Here we show that FMRP is a substrate of the small ubiquitin-like modifier (SUMO) pathway in the brain and identify its active SUMO sites. We unravel the functional consequences of FMRP sumoylation in neurons by combining molecular replacement strategy, biochemical reconstitution assays with advanced live-cell imaging. We first demonstrate that FMRP sumoylation is promoted by activation of metabotropic glutamate receptors. We then show that this increase in sumoylation controls the homomerization of FMRP within dendritic mRNA granules which, in turn, regulates spine elimination and maturation. Altogether, our findings reveal the sumoylation of FMRP as a critical activity-dependent regulatory mechanism of FMRP-mediated neuronal function.

Date: 2018
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DOI: 10.1038/s41467-018-03222-y

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