Decoding sORF translation - from small proteins to gene regulation

Abstract

Translation is best known as the fundamental mechanism by which the ribosome converts a sequence of nucleotides into a string of amino acids. Extensive research over many years has elucidated the key principles of translation, and the majority of translated regions were thought to be known. The recent discovery of wide-spread translation outside of annotated protein-coding open reading frames (ORFs) came therefore as a surprise, raising the intriguing possibility that these newly discovered translated regions might have unrecognized protein-coding or gene-regulatory functions. Here, we highlight recent findings that provide evidence that some of these newly discovered translated short ORFs (sORFs) encode functional, previously missed small proteins, while others have regulatory roles. Based on known examples we will also speculate about putative additional roles and the potentially much wider impact that these translated regions might have on cellular homeostasis and gene regulation.

Keywords: Ribosome; sORF; short proteins; translation; translational regulation; uORF.

Figure 1.

sORFs as source of functional short proteins. Translation of short open reading frames (sORFs) can generate short proteins (light blue sphere) with diverse intracellular and extracellular roles. Functions range from cytoplasmic regulation of enzymes, protein-protein interactions, enzymatic activities to regulation of transcription factors in the nucleus and extracellular roles as signals, membrane-associated proteins or antigens presented on MHC-type molecules.

Figure 2.

uORFs as post-transcriptional regulators of gene expression. Translation of sORFs upstream of the main coding sequence (CDS, dark blue), so-called upstream ORFs (uORFs, light blue), is generally repressive by blocking the ribosome from accessing the downstream CDS. Two strategies allow the cell to bypass the inhibitory effect of uORFs (dashed arrows): leaky scanning and reinitiation. 80S, actively translating ribosome; 60S, large ribosomal subunit; 40S, small ribosomal subunit; 43S, preinitiation complex.