The proteome under translational control

Abstract

A single eukaryotic gene can give rise to a variety of protein forms (proteoforms) as a result of genetic variation and multilevel regulation of gene expression. In addition to alternative splicing, an increasing line of evidence shows that alternative translation contributes to the overall complexity of proteomes. Identifying the repertoire of proteins and micropeptides expressed by alternative selection of (near-)cognate translation initiation sites and different reading frames however remains challenging with contemporary proteomics. MS-enabled identification of proteoforms is expected to benefit from transcriptome and translatome data by the creation of customized and sample-specific protein sequence databases. Here, we focus on contemporary integrative omics approaches that complement proteomics with DNA- and/or RNA-oriented technologies to elucidate the mechanisms of translational control. Together, these technologies enable to map the translation (initiation) landscape and more comprehensively define the inventory of proteoforms raised upon alternative translation, thus assisting in the (re-)annotation of genomes.

Ultra-deep sequencing of ribosome-associated poly-adenylated RNA in earlyDrosophilaembryos reveals hundreds of conserved translated sORFs

“…For example, with the gene CG40228 , we found five isoforms with (in total) 3 different sORFs, including a variant isoform not previously characterized with a unique 5′ untranslated region (UTR) that is 19 bp upstream of all other isoforms. Variant isoforms in longer ORFs are usually associated with their highly regulated, differential translation, 59 , 60 and so this observation of variant sORF isoforms suggests that the translational processing of the sORFs may be as complex as that governing their longer counterpart. Ribosome profiling might prove useful in this regard, since a recent study employing this method thoroughly characterized stop codon readthrough in many genes in early Drosophila embryos 61 …”

Maize reas1 Mutant Stimulates Ribosome Use Efficiency and Triggers Distinct Transcriptional and Translational Responses

“…The translation of individual mRNAs is regulated, producing discrepancies between mRNA and protein levels. mRNAs have a distinct pattern of ribosome loading under certain conditions, resulting in altered translational efficiencies (Branco-Price et al, 2005;Gawron et al, 2014). Thus, analysis of transcript level is insufficient to completely describe cellular responses under different conditions.…”

Control of Gene Expression by RNA Binding Protein Action on Alternative Translation Initiation Sites

“…The presence of uORFs is known to regulate translation of primary downstream ORFs by operating via decay, re-initiation, or peptide-mediated ribosomal stalling during uORF translation [55],[65],[25]. Although uORFs can regulate protein levels without involving RBPs [65], an already cited previous study in Drosophila offers an example where the SXL RBP promotes translation initiation at the uORF of the msl-2 and Irr47 transcripts [61], which thus results in translational repression. More recently, the DENR-MCT-1 complex has been identified as a regulator of eukaryotic uORF-dependent translation re-initiation of a specific group of mRNAs [34].…”