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Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling

Author

Listed:
  • Biljana Ermanoska

    (University of Antwerp
    University of Antwerp
    Brandeis University)

  • Bob Asselbergh

    (VIB Center for Molecular Neurology, VIB
    University of Antwerp)

  • Laura Morant

    (University of Antwerp
    University of Antwerp)

  • Maria-Luise Petrovic-Erfurth

    (University of Antwerp
    University of Antwerp)

  • Seyyedmohsen Hosseinibarkooie

    (University Hospital of Cologne; University of Cologne
    University of Virginia)

  • Ricardo Leitão-Gonçalves

    (University of Antwerp
    University of Antwerp
    Frontiers Media SA)

  • Leonardo Almeida-Souza

    (University of Antwerp
    University of Antwerp
    University of Helsinki)

  • Sven Bervoets

    (University of Antwerp
    University of Antwerp
    University of Utah)

  • Litao Sun

    (The Scripps Research Institute
    Sun Yat-Sen University)

  • LaTasha Lee

    (Florida Atlantic University
    National Minority Quality Forum)

  • Derek Atkinson

    (University of Antwerp
    University of Antwerp
    Max Planck Institute of Immunobiology and Epigenetics)

  • Akram Khanghahi

    (University of Antwerp
    University of Antwerp)

  • Ivaylo Tournev

    (Medical University-Sofia
    New Bulgarian University)

  • Patrick Callaerts

    (KU Leuven)

  • Patrik Verstreken

    (VIB-KU Leuven Center for Brain & Disease Research
    Leuven Brain Institute, Mission Lucidity)

  • 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
    University of Antwerp
    Medical University-Sofia)

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.

Suggested Citation

  • Biljana Ermanoska & Bob Asselbergh & Laura Morant & Maria-Luise Petrovic-Erfurth & Seyyedmohsen Hosseinibarkooie & Ricardo Leitão-Gonçalves & Leonardo Almeida-Souza & Sven Bervoets & Litao Sun & LaTas, 2023. "Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35908-3
    DOI: 10.1038/s41467-023-35908-3
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    References listed on IDEAS

    as
    1. Sven Bervoets & Na Wei & Maria-Luise Erfurth & Shazie Yusein-Myashkova & Biljana Ermanoska & Ligia Mateiu & Bob Asselbergh & David Blocquel & Priyanka Kakad & Tyrone Penserga & Florian P Thomas & Veli, 2019. "Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Weiwei He & Ge Bai & Huihao Zhou & Na Wei & Nicholas M. White & Janelle Lauer & Huaqing Liu & Yi Shi & Calin Dan Dumitru & Karen Lettieri & Veronica Shubayev & Albena Jordanova & Velina Guergueltcheva, 2015. "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase," Nature, Nature, vol. 526(7575), pages 710-714, October.
    3. Sven Niehues & Julia Bussmann & Georg Steffes & Ines Erdmann & Caroline Köhrer & Litao Sun & Marina Wagner & Kerstin Schäfer & Guangxia Wang & Sophia N. Koerdt & Morgane Stum & Sumit Jaiswal & Uttam L, 2015. "Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    4. Lujia Zhou & Joseph McInnes & Keimpe Wierda & Matthew Holt & Abigail G. Herrmann & Rosemary J. Jackson & Yu-Chun Wang & Jef Swerts & Jelle Beyens & Katarzyna Miskiewicz & Sven Vilain & Ilse Dewachter , 2017. "Tau association with synaptic vesicles causes presynaptic dysfunction," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
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