A threonyl-tRNA synthetase-mediated translation initiation machinery

Seung Jae Jeong,Eun-Young Lee,Jeong-Soo Lee,Ina Yoon,Hoi Kyoung Kim,Won Suk Yang,Nahum Sonenberg,Chan Yong Lee,Ji-Hyun Lee,Jungwon Hwang,Jong Hyun Kim,Myung Hee Kim,Shinhye Park,Seon-Young Kim,Doyeun Kim,Loi T Nguyen,Kweon Yu,Sunghoon Kim,Hoi-Khoanh Giong

doi:10.1038/s41467-019-09086-0

Abstract

A fundamental question in biology is how vertebrates evolved and differ from invertebrates, and little is known about differences in the regulation of translation in the two systems. Herein, we identify a threonyl-tRNA synthetase (TRS)-mediated translation initiation machinery that specifically interacts with eIF4E homologous protein, and forms machinery that is structurally analogous to the eIF4F-mediated translation initiation machinery via the recruitment of other translation initiation components. Biochemical and RNA immunoprecipitation analyses coupled to sequencing suggest that this machinery emerged as a gain-of-function event in the vertebrate lineage, and it positively regulates the translation of mRNAs required for vertebrate development. Collectively, our findings demonstrate that TRS evolved to regulate vertebrate translation initiation via its dual role as a scaffold for the assembly of initiation components and as a selector of target mRNAs. This work highlights the functional significance of aminoacyl-tRNA synthetases in the emergence and control of higher order organisms.

Highlights

A fundamental question in biology is how vertebrates evolved and differ from invertebrates, and little is known about differences in the regulation of translation in the two systems
In addition to its tRNAcharging activity, Escherichia coli tRNA synthetase (TRS) represses the translation of its own mRNA by binding to the 5′ untranslated region (UTR), which forms a pseudoanticodon loop[11]
Of the 434 proteins identified as potential direct or indirect TRS-interacting components, factors involved in post-transcriptional regulation (88), mRNA metabolic process (91), and translation (83) were enriched with high statistical significance (Supplementary Fig. 1a, b)

Summary

Introduction

A fundamental question in biology is how vertebrates evolved and differ from invertebrates, and little is known about differences in the regulation of translation in the two systems. Oxygen tension-specific translation initiation during hypoxia is triggered when the cap-dependent translation machinery switches from eIF4E to eIF4E2 ( known as eIF4E homologous protein, 4EHP), which assembles together with oxygen-regulated hypoxia-inducible factor 2α (HIF-2α) and RNA-binding protein RBM4 into a hypoxia-stimulated heterotrimeric complex that regulates global hypoxic protein synthesis[5]. These findings demonstrate the potential for fundamental complexity in protein synthesis via alternative translation machineries, but detailed molecular mechanisms remain poorly understood. TRS exhibits dual functionality to determine the vertebrate specificity of the machinery via its unique N-terminal extension that represents a gain-of-function component, and its ability to select target mRNAs

Methods

Results

Conclusion