Control of translation elongation in health and disease

Abstract

Regulation of protein synthesis makes a major contribution to posttranscriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)-and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.

Manipulation of the human tRNA pool reveals distinct tRNA sets that act in cellular proliferation or cell cycle arrest

“…The regulatory network that controls the proliferation and cell arrest, and the balance between them have been heavily investigated, yet predominantly at the transcription level since data is mostly available at the RNA level (Bar-joseph et al, 2008;Nagano et al, 2016;Hafner et al, 2017;Hernandez-Segura et al, 2017;Casella et al, 2019). mRNA translation on the other hand, specifically translation elongation, though studied extensively too (Patil et al, 2012;Aviner et al, 2015;Rapino et al, 2018;Bludau and Aebersold, 2020;Knight et al, 2020) remain less characterized in these systems. tRNAs are a key molecular entity that converts the transcriptome into the proteome.…”

Cdk5 regulatory subunit-associated protein 1 knockout mice show hearing loss phenotypically similar to age-related hearing loss

“…The nucleotides of transfer RNAs (tRNAs) are often post-transcriptionally modified by various enzymatic reactions [ 11 ] that are critical for efficient and accurate decoding, especially as they improve tRNA–codon binding [ 12 , 13 ]. Numerous human diseases such as type 2 diabetes and mitochondrial diseases have been linked to deficient modifications of the mitochondrial tRNAs (mt-tRNAs) [ 9 – 11 , 14 – 20 ]. Dysregulation of tRNA modifications is also thought to precede aging in human [ 9 , 10 ].…”

“…Numerous human diseases such as type 2 diabetes and mitochondrial diseases have been linked to deficient modifications of the mitochondrial tRNAs (mt-tRNAs) [ 9 – 11 , 14 – 20 ]. Dysregulation of tRNA modifications is also thought to precede aging in human [ 9 , 10 ]. Furthermore, mammalian mt-tRNAs are modified by nuclear tRNA-modifying enzymes such as Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1), which catalyzes the deposition of the 2-methylthio (ms 2 ) modifications on the mammalian mt-tRNAs [ 16 , 21 ] (Fig.…”

Structural features and development of an assay platform of the parasite target deoxyhypusine synthase of Brugia malayi and Leishmania major

“…In a second reaction, production of mature, active eIF5A is carried out by deoxyhypusine hydroxylase (DOOH). In eukaryotic cells, mature eIF5A is required for translation elongation and termination, and essential for cell viability [11]. Likewise, DHS is thought to be essential in all eukaryotes [12], and gene knock-out experiments have shown DHS function to be essential for Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei [13][14][15].…”