Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy

Ligia Mateiu,Xiang-Lei Yang,Biljana Ermanoska,David Blocquel,Sven Bervoets,Velina Guergueltcheva,Albena Jordanova,Na Wei,Bob Asselbergh,Tyrone Penserga,Tanja Godenschwege,Florian P Thomas,Shazie Yusein-Myashkova,Priyanka Kakad,Ivailo Tournev,Maria-Luise Erfurth

doi:10.1038/s41467-019-12909-9

Abstract

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.

Highlights

Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy
While the early hypothesis was that nuclear aminoacyl-tRNA synthetases (aaRSs) function in proofreading newly-synthesized tRNAs4–6, later findings suggest that they are involved in regulating a wide range of biological processes including vascular development, inflammation, and stress responses mainly due to their peculiar abilities to interact with the transcriptional machinery[7,8,9]
We demonstrated that the three established CMT-causing TyrRS mutants (TyrRS-E196K, TyrRS-G41R, and TyrRS-Δ153-156VKQV) induce a conformational opening and expose a consensus area in the catalytic domain of the enzyme[17] (Fig. 1a, b)

Summary

Introduction

Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. 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. Three have been extensively characterized both in vitro and in vivo and the results show that a defect in aminoacylation activity is not a shared property (i.e., TyrRS-G41R is enzymatically inactive, while TyrRS-E196K is fully active, and TyrRS-Δ153-156VKQV has partial activity), suggesting that a simple loss of canonical function is not a prerequisite for the disease to occur[14] Pathogenicity of these three mutations has been recapitulated in transgenic Drosophila models displaying progressive loss of motor abilities, electrophysiological neuronal dysfunction, and terminal axonal degeneration[15]. Flies expressing the enzymatically intact TyrRS-E196K mutant show comparable or, in some aspects, more pronounced features of neurodegeneration than flies expressing the aminoacylation compromised mutants, indicating that a gain of toxic function or interference with a non-enzymatic function of the wild type (WT) protein is likely underlying the disease[15]

Methods

Results

Conclusion