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- Title
Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
- Authors
Ermanoska, Biljana; Asselbergh, Bob; Morant, Laura; Petrovic-Erfurth, Maria-Luise; Hosseinibarkooie, Seyyedmohsen; Leitão-Gonçalves, Ricardo; Almeida-Souza, Leonardo; Bervoets, Sven; Sun, Litao; Lee, LaTasha; Atkinson, Derek; Khanghahi, Akram; Tournev, Ivaylo; Callaerts, Patrick; Verstreken, Patrik; Yang, Xiang-Lei; Wirth, Brunhilde; Rodal, Avital A.; Timmerman, Vincent; Goode, Bruce L.
- 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. Mutations in tRNA ligases, essential components of the translational machinery, are associated with Charcot-Marie-Tooth peripheral neuropathy, but the mechanistic details are not known. The authors report that the tyrosyl-tRNA synthetase is an evolutionary-conserved F-actin organizer, and dysregulation of this function is associated with the disorder.
- Subjects
TRANSFER RNA; ACTIN; CYTOSKELETON; GENETIC testing; PERIPHERAL neuropathy; F-actin; UBIQUITIN ligases
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-35908-3