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; Albena Jordanova

doi:10.1038/s41467-023-35908-3

Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling

Nat Commun. 2023 Mar 8;14(1):999. doi: 10.1038/s41467-023-35908-3.

Authors

Biljana Ermanoska^{1

2

3}, Bob Asselbergh^{4

5}, Laura Morant^{1

2}, Maria-Luise Petrovic-Erfurth^{1

2}, Seyyedmohsen Hosseinibarkooie^{6

7}, Ricardo Leitão-Gonçalves^{1

2

8}, Leonardo Almeida-Souza^{1

2

9}, Sven Bervoets^{1

2

10}, Litao Sun^{11

12}, LaTasha Lee^{13

14}, Derek Atkinson^{1

2

15}, Akram Khanghahi^{1

2}, Ivaylo Tournev^{16

17}, Patrick Callaerts¹⁸, Patrik Verstreken^{19

20}, Xiang-Lei Yang¹¹, Brunhilde Wirth⁶, Avital A Rodal³, Vincent Timmerman², Bruce L Goode³, Tanja A Godenschwege¹³, Albena Jordanova^{21

22

23}

Affiliations

¹ Center for Molecular Neurology, VIB, University of Antwerp, 2610, Antwerpen, Belgium.
² Department of Biomedical Sciences, University of Antwerp, 2610, Antwerpen, Belgium.
³ Department of Biology, Brandeis University, Waltham, MA, 02453, USA.
⁴ Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, 2610, Antwerp, Belgium.
⁵ Neuromics Support Facility, Department of Biomedical Sciences, University of Antwerp, 2610, Antwerp, Belgium.
⁶ Institute of Human Genetics; Center for Molecular Medicine Cologne; Center for Rare Diseases Cologne, University Hospital of Cologne; University of Cologne, 50931, Cologne, Germany.
⁷ Division of Endocrinology and Metabolism and Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
⁸ Frontiers Media SA, Lausanne, Switzerland.
⁹ Helsinki Institute of Life Science, Institute of Biotechnology & Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
¹⁰ Department of Neurobiology, University of Utah, Salt Lake City, UT, USA.
¹¹ Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
¹² School of Public Health (Shenzhen), Sun Yat-Sen University, Guangdong, China.
¹³ Department of Biological Sciences, Florida Atlantic University, Jupiter, FL, 33458, USA.
¹⁴ Center for Social and Clinical Research, National Minority Quality Forum, Washington, DC, USA.
¹⁵ Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
¹⁶ Department of Neurology, Medical University-Sofia, 1431, Sofia, Bulgaria.
¹⁷ Department of Cognitive Science and Psychology, New Bulgarian University, 1618, Sofia, Bulgaria.
¹⁸ Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.
¹⁹ VIB-KU Leuven Center for Brain & Disease Research, 3000, Leuven, Belgium.
²⁰ KU Leuven, Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, 3000, Leuven, Belgium.
²¹ Center for Molecular Neurology, VIB, University of Antwerp, 2610, Antwerpen, Belgium. [email protected].
²² Department of Biomedical Sciences, University of Antwerp, 2610, Antwerpen, Belgium. [email protected].
²³ Department of Medical Chemistry and Biochemistry, Medical University-Sofia, 1431, Sofia, Bulgaria. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins* / metabolism
Animals
Cell Line, Tumor
Charcot-Marie-Tooth Disease / genetics
Drosophila / genetics
Glycine-tRNA Ligase / genetics
Humans
Mutation
RNA, Transfer
Tyrosine-tRNA Ligase* / genetics
Tyrosine-tRNA Ligase* / metabolism

Substances

Actins
Glycine-tRNA Ligase
RNA, Transfer
Tyrosine-tRNA Ligase

Abstract

Publication types

MeSH terms

Substances

Grants and funding