Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 03 2023
08 03 2023
Historique:
received:
06
02
2022
accepted:
06
01
2023
entrez:
8
3
2023
pubmed:
9
3
2023
medline:
11
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36890170
doi: 10.1038/s41467-023-35908-3
pii: 10.1038/s41467-023-35908-3
pmc: PMC9995517
doi:
Substances chimiques
Actins
0
Glycine-tRNA Ligase
EC 6.1.1.14
RNA, Transfer
9014-25-9
Tyrosine-tRNA Ligase
EC 6.1.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
999Subventions
Organisme : NICHD NIH HHS
ID : R01 HD050725
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS120123
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134895
Pays : United States
Informations de copyright
© 2023. The Author(s).
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