Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling

Biljana Ermanoska, Bob Asselbergh, Laura Morant, Maria-Luise Petrovic-Erfurth, Seyyedmohsen Hosseinibarkooie, Ricardo Leitão-Gonçalves, Leonardo Almeida-Souza, Sven Bervoets, Litao Sun, LaTasha Lee, Derek Atkinson, Akram Khanghahi, Ivaylo Tournev, Patrick Callaerts, Patrik Verstreken, Xiang-Lei Yang, Brunhilde Wirth, Avital A. Rodal, Vincent Timmerman, Bruce L. Goode, Tanja A. Godenschwege and Albena Jordanova ()
Additional contact information
Biljana Ermanoska: University of Antwerp
Bob Asselbergh: VIB Center for Molecular Neurology, VIB
Laura Morant: University of Antwerp
Maria-Luise Petrovic-Erfurth: University of Antwerp
Seyyedmohsen Hosseinibarkooie: University Hospital of Cologne; University of Cologne
Ricardo Leitão-Gonçalves: University of Antwerp
Leonardo Almeida-Souza: University of Antwerp
Sven Bervoets: University of Antwerp
Litao Sun: The Scripps Research Institute
LaTasha Lee: Florida Atlantic University
Derek Atkinson: University of Antwerp
Akram Khanghahi: University of Antwerp
Ivaylo Tournev: Medical University-Sofia
Patrick Callaerts: KU Leuven
Patrik Verstreken: VIB-KU Leuven Center for Brain & Disease Research
Xiang-Lei Yang: The Scripps Research Institute
Brunhilde Wirth: University Hospital of Cologne; University of Cologne
Avital A. Rodal: Brandeis University
Vincent Timmerman: University of Antwerp
Bruce L. Goode: Brandeis University
Tanja A. Godenschwege: Florida Atlantic University
Albena Jordanova: University of Antwerp

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in the Drosophila nervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration.

Date: 2023
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DOI: 10.1038/s41467-023-35908-3

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