Keywords :
Amino Acids/chemistry/genetics/metabolism; Cell Line, Tumor; Codon Usage; Gene Knockdown Techniques; Humans; Hydrophobic and Hydrophilic Interactions; Multienzyme Complexes/genetics/metabolism; Peptide Chain Elongation, Translational; Protein Aggregates/genetics; Proteolysis; Proteomics; RNA Processing, Post-Transcriptional; RNA, Messenger/metabolism; RNA, Transfer/genetics/metabolism; Uridine/metabolism
Abstract :
[en] Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm(5)s(2) wobble uridine tRNA modification (U(34)-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U(34)-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U(34)-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.
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