Metabolite Control of Translation by Conserved Peptide uORFs: The Ribosome as a Metabolite Multi-sensor

The regulation of gene expression is intensely investigated in diverse biological systems. Gene expression involves RNA transcription, RNA splicing, RNA stability, translation, posttranslational modification and protein stability. Particular attention has been given to mRNA levels due to advances in microarray analysis and RNA-sequencing techniques. However, transcript levels do not necessarily correlate with protein levels or functionality (Conrads et al., 2005; Gibon et al., 2006; Bianchini et al., 2008) and complex layers of posttranscriptional regulation have been uncovered, foremost mRNA translation. Translation can be regulated both globally and in a transcript-specific manner. Examples of global mRNA translational regulation include availability of ribosomes, and translation initiation, elongation and termination factors. In transcript-specific translational regulation individual mRNA species or mRNA groups are selectively translated. For example, mRNAs can be sequestered in stress granules, removing them from the translatable mRNA pool (Chantarachot and Bailey-Serres, 2017). mRNA sequence or structural features can affect translatability directly or indirectly, the latter via small RNAs or mRNA binding proteins (reviewed in Merchante et al., 2017). Upstream open reading frames (uORFs) have been shown to participate in both global and transcript-specific regulation (Von Arnim et al., 2014). Here, recent advances in translation regulation by uORFs are discussed, focusing on uORFs encoding sequence conserved peptides (CPuORFs).