Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling

被引：7

作者：

Ermanoska, Biljana ^{[1
,2
,3
]}

Asselbergh, Bob ^{[4
,5
]}

Morant, Laura ^{[1
,2
]}

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

Hosseinibarkooie, Seyyedmohsen ^{[6
,7
,8
,9
,18
,19
]}

Leitao-Goncalves, Ricardo ^{[1
,2
,20
]}

Almeida-Souza, Leonardo ^{[1
,2
,21
,22
]}

Bervoets, Sven ^{[1
,2
,23
]}

Sun, Litao ^{[10
,24
]}

Lee, LaTasha ^{[11
,25
]}

Atkinson, Derek ^{[1
,2
,26
]}

Khanghahi, Akram ^{[1
,2
]}

Tournev, Ivaylo ^{[12
,13
]}

Callaerts, Patrick ^{[14
]}

Verstreken, Patrik ^{[15
,16
]}

Yang, Xiang-Lei ^{[10
]}

Wirth, Brunhilde ^{[6
,7
,8
,9
]}

Rodal, Avital A. ^{[3
]}

Timmerman, Vincent ^{[2
]}

Goode, Bruce L. ^{[3
]}

Godenschwege, Tanja A. ^{[11
]}

Jordanova, Albena ^{[1
,2
,17
]}

机构：

[1] Univ Antwerp, Ctr Mol Neurol, VIB, B-2610 Antwerp, Belgium

[2] Univ Antwerp, Dept Biomed Sci, B-2610 Antwerp, Belgium

[3] Brandeis Univ, Dept Biol, Waltham, MA 02453 USA

[4] VIB, VIB Ctr Mol Neurol, Neur Support Facil, B-2610 Antwerp, Belgium

[5] Univ Antwerp, Dept Biomed Sci, Neur Support Facil, B-2610 Antwerp, Belgium

[6] Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany

[7] Univ Hosp Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[8] Univ Hosp Cologne, Ctr Rare Dis Cologne, D-50931 Cologne, Germany

[9] Univ Cologne, D-50931 Cologne, Germany

[10] Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA

[11] Florida Atlantic Univ, Dept Biol Sci, Jupiter, FL 33458 USA

[12] Med Univ Sofia, Dept Neurol, Sofia 1431, Bulgaria

[13] New Bulgarian Univ, Dept Cognit Sci & Psychol, Sofia 1618, Bulgaria

[14] Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium

[15] VIB KU Leuven Ctr Brain & Dis Res, B-3000 Leuven, Belgium

[16] Katholieke Univ Leuven, Leuven Brain Inst, Dept Neurosci, Mission Lucid, B-3000 Leuven, Belgium

[17] Med Univ Sofia, Dept Med Chem & Biochem, Sofia 1431, Bulgaria

[18] Univ Virginia, Div Endocrinol & Metab, Charlottesville, VA USA

[19] Univ Virginia, Dept Neurosci, Charlottesville, VA USA

[20] Frontiers Media SA, Lausanne, Switzerland

[21] Univ Helsinki, Helsinki Inst Life Sci, Inst Biotechnol, Helsinki, Finland

[22] Univ Helsinki, Fac Biol & Environm Sci, Helsinki, Finland

[23] Univ Utah, Dept Neurobiol, Salt Lake City, UT USA

[24] Sun Yat Sen Univ, Sch Publ Hlth Shenzhen, Guangzhou, Guangdong, Peoples R China

[25] Natl Minor Qual Forum, Ctr Social & Clin Res, Washington, DC USA

[26] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

欧洲研究理事会;

关键词：

F-ACTIN; DROSOPHILA; MUTATIONS; PROTEIN; TOOL; ORGANIZATION; CYTOSKELETON; DISEASE; ASSOCIATION; TOXICITY;

D O I：

10.1038/s41467-023-35908-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：19

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