Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy.
Amino Acyl-tRNA Synthetases
/ genetics
Animals
Animals, Genetically Modified
Behavior, Animal
Cell Nucleus
/ enzymology
Charcot-Marie-Tooth Disease
/ genetics
Disease Models, Animal
Drosophila
Drosophila Proteins
/ metabolism
Female
Genetic Predisposition to Disease
HEK293 Cells
Humans
Larva
Male
Mutation
Nervous System Diseases
Neuromuscular Junction
Neurons
/ metabolism
Phenotype
Transcription Factors
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 11 2019
06 11 2019
Historique:
received:
26
02
2019
accepted:
01
10
2019
entrez:
8
11
2019
pubmed:
7
11
2019
medline:
3
3
2020
Statut:
epublish
Résumé
Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.
Identifiants
pubmed: 31695036
doi: 10.1038/s41467-019-12909-9
pii: 10.1038/s41467-019-12909-9
pmc: PMC6834567
doi:
Substances chimiques
Drosophila Proteins
0
E2f1 protein, Drosophila
0
Transcription Factors
0
Amino Acyl-tRNA Synthetases
EC 6.1.1.-
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
5045Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM088278
Pays : United States
Organisme : NINDS NIH HHS
ID : R15 NS090043
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS085092
Pays : United States
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