PXD037630

PXD037630 is an original dataset announced via ProteomeXchange.

Title	A non-canonical function of tyrosyl-tRNA synthetase in actin bundling
Description	Aminoacyl-tRNA synthetases are the largest protein family implicated in Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy that is currently incurable. These essential enzymes catalyze the attachment of amino acids to their cognate tRNAs, thereby enabling the protein biosynthesis in every cell. Surprisingly, loss of aminoacylation is not a prerequisite for CMT to occur, suggesting a disease mechanism associated with a gain of neurotoxic function. Via an unbiased genetic modifier screen in a Drosophila model of tyrosyl-tRNA synthetase (YARS) -induced CMT, we established a link between the tRNA-ligase and regulators of actin cytoskeleton. By investigating the interactome of YARS in cellulo we found this synthetase to be enriched in protein complexes containing actin and actin-modifying proteins. Follow up in vitro and in vivo studies demonstrated that YARS itself has not only actin binding- but also actin-bundling properties independent of its aminoacylation function. These non-canonical activities are evolutionary conserved and contribute to the organization of actin cytoskeleton in Drosophila neurons and in patient-derived cells. An enzymatically active YARSCMT mutant caused stronger actin bundling in vitro, disorganization of actin bundle-rich stress fibers in patient-derived cells and impaired multiple actin-based steps of the synaptic vesicle cycle in fly neurons. Genetic modulation of the F-actin organization state restored synaptic vesicle mobility and rescued hallmark electrophysiological and morphological features in the neurons of fruit flies expressing different YARSCMT mutations. Thus, we uncover a role of tyrosyl-tRNA synthetase in actin organization that is implicated in the CMT neuropathy.
HostingRepository	PRIDE
AnnounceDate	2023-01-09
AnnouncementXML	Submission_2023-01-09_06:41:29.006.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SeyyyedmohsenHosseinibarkooie
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-20 13:45:36	ID requested
⏵ 1	2023-01-09 06:41:29	announced

Dataset with its publication pending

submitter keyword: YARS,HEK293t cells

AlbenaJordanova
contact affiliation	VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria
contact email	Albena.Jordanova@uantwerpen.vib.be
lab head
SeyyyedmohsenHosseinibarkooie
contact affiliation	University of Virginia
contact email	sh4hj@virginia.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD037630
     1. Label: PRIDE project
     2. Name: A non-canonical function of tyrosyl-tRNA synthetase in actin bundling