Minimum-noise production of translation factor eIF4G maps to a mechanistically determined optimal rate control window for protein synthesis.

Xiang Meng,Pedro Mendes,John E.G Mccarthy,Helena Firczuk,Paola Pietroni,Richard Westbrook,Estelle Dacheux

doi:10.1093/nar/gkw1194

Xiang Meng, Pedro Mendes + Show 5 more

Open Access

https://doi.org/10.1093/nar/gkw1194

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Abstract

Gene expression noise influences organism evolution and fitness. The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis. We observe an asymmetric, approximately bell-shaped, relationship between the average intracellular abundance of eIF4G and rates of cell population growth and global mRNA translation, with peak rates occurring at normal physiological abundance. This relationship fits a computational model in which eIF4G is at the core of a multi-component–complex assembly pathway. This model also correctly predicts a plateau-like response of translation to super-physiological increases in abundance of the other cap-complex factors, eIF4E and eIF4A. Engineered changes in eIF4G abundance amplify noise, demonstrating that minimum stochasticity coincides with physiological abundance of this factor. Noise is not increased when eIF4E is overproduced. Plasmid-mediated synthesis of eIF4G imposes increased global gene expression stochasticity and reduced viability because the intrinsic noise for this factor influences total cellular gene noise. The naturally evolved eIF4G gene expression noise minimum maps within the optimal activity zone dictated by eIF4G's mechanistic role. Rate control and noise are therefore interdependent and have co-evolved to share an optimal physiological abundance point.

Highlights

It is estimated that more than 76% of yeast’s total cellular energy budget is committed to protein synthesis [1]
The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis
Imprecision in the control of protein synthesis is a potential threat to organism survival; gene expression noise generated via the translation machinery can be expected to influence the viability of individual cells

Summary

Introduction

It is estimated that more than 76% of yeast’s total cellular energy budget is committed to protein synthesis [1]. Imprecision in the control of protein synthesis is a potential threat to organism survival; gene expression noise generated via the translation machinery can be expected to influence the viability of individual cells. To place this into context, recent modeling work has estimated the effective cost of noise as equivalent to up to 25% of overall yeast fitness [3]. EIF4E and eIF4G, together with the DEAD-box helicase eIF4A (encoded by TIF1 and TIF2), form the cap-binding complex eIF4F (Figure 1A), and eIF4G-Pab interactions are capable of mediating interactions between the 5 and 3 ends of mRNA [5].

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