Translation Initiation Regulated by RNA-Binding Protein in Mammals: The Modulation of Translation Initiation Complex by Trans-Acting Factors.

Akira Fukao,Toshinobu Fujiwara,Takumi Tomohiro

doi:10.3390/cells10071711

Abstract

Protein synthesis is tightly regulated at each step of translation. In particular, the formation of the basic cap-binding complex, eukaryotic initiation factor 4F (eIF4F) complex, on the 5′ cap structure of mRNA is positioned as the rate-limiting step, and various cis-elements on mRNA contribute to fine-tune spatiotemporal protein expression. The cis-element on mRNAs is recognized and bound to the trans-acting factors, which enable the regulation of the translation rate or mRNA stability. In this review, we focus on the molecular mechanism of how the assembly of the eIF4F complex is regulated on the cap structure of mRNAs. We also summarize the fine-tuned regulation of translation initiation by various trans-acting factors through cis-elements on mRNAs.

Highlights

Expression of genetic information that is transcribed from DNA into mRNA is controlled by complicated and sophisticated regulatory systems with various RNA-binding trans-acting factors (e.g., RNA-binding proteins and microRNAs) and determines higher order vital cellular phenomena in eukaryotes
Among these post-transcriptional gene expression regulations, fine-tuning of spatiotemporal protein synthesis is essential for cell growth, development, and differentiation
The regulation of the translation initiation step is very efficient because this step is the rate-limiting step of protein synthesis

Summary

Introduction

The cap-dependent, canonical translation is initiated when the eukaryotic translation initiation factor (eIF) 4F complex is assembled on the 50 cap of mRNAs. The eIF4F complex consists of eIF4E (cap-binding), eIF4G (platform for eIFs), and eIF4A (RNA unwinding). Since the formation of the eIF4F complex (including eIF4G/PABP interaction) is a rate-limiting step of cap-dependent translation initiation, it is a molecular target of translational control (Figure 1). Some trans-acting factors, such as RNA-binding proteins and microRNAs (miRNAs), regulate translation through the direct or indirect interaction with a basic cap-binding complex to modulate the translation initiation complex. This review summarizes the molecular mechanism of translation regulation via the stability control of the cap-binding complex by trans-acting factors and cis-elements on mRNA. 43S PIC consists of 40S, a small ribosomal subunit, and several eIFs, such as eIF3 and eIF2

RNA-Binding Protein-Mediated Translation Regulation

Translation Regulation via PABP-Binding

Translation Regulation via Phosphorylation of RNA-Binding Proteins

Conclusions