Near-Cognate Codons Contribute Complexity to Translation Regulation.

N Louise Glass

doi:10.1128/mbio.01820-17

Abstract

ABSTRACTThe interplay between translation initiation, modification of translation initiation factors, and selection of start sites on mRNA for protein synthesis can play a regulatory role in the cellular response to stress, development, and cell fate in eukaryotic species by shaping the proteome. As shown by Ivanov et al. (mBio 8:e00844-17, 2017, https://doi.org/10.1128/mBio.00844-17), in the filamentous fungus Neurospora crassa, both upstream open reading frames (uORFs) and near-cognate start codons negatively or positively regulate the translation of the transcription factor CPC1 and production of CPC1 isoforms, which mediate the cellular response to amino acid starvation. Dissecting the physiological roles that differentiate cellular choice of translation initiation is an important parameter to understanding mechanisms that determine cell fate via gene regulation and protein synthesis.

Highlights

Translational control of protein synthesis in eukaryotic cells is a well-known phenomenon, with noncanonical initiation events controlling gene expression of coding regions
Despite the widespread occurrence of upstream open reading frames (uORFs) in eukaryotic mRNA, biochemical and genetic evidence for a regulatory role for 5= leader region uORFs on translation of downstream ORFs has been shown for relatively few genes
Two uORFs in the 5= untranslated region (UTR) of GCN4 mRNA play pivotal regulatory roles. uORF1 acts as a positive regulatory element to facilitate reinitiation at the start codon for the GCN4 protein coding ORF, while uORF4 strongly inhibits the translation of GCN4 by preventing reinitiation

Summary

Introduction

Translational control of protein synthesis in eukaryotic cells is a well-known phenomenon, with noncanonical initiation events controlling gene expression of coding regions. GCN4 in other fungi contain at least two uORFs believed to have similar regulatory functions as the S. cerevisiae GCN4 uORFs. In addition to these regulatory uORFs, kinases such as Gcn2 play a regulatory role in GCN4 expression; phosphorylation of the translation initiation factor eIF2␣ (␣ subunit of eukaryotic initiation factor 2) by Gcn2 kinase increases reinitiation at the GCN4 protein coding start codon in response to amino acid limitation [11].

Results

Conclusion