Dr. Sebastian Leidel, Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Germany
Tuesday 3rd November, 1.00 p.m., Keynes Lecture Theatre 6
Proteins start to fold as they emerge from translating ribosomes. The kinetics of ribosome transit along a given mRNA can influence nascent chain folding, but the extent to which individual codon translation rates impact proteome integrity remains unknown. Here we show that slower decoding of distinct codons profoundly impairs protein homeostasis and elicits widespread protein aggregation in vivo. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs leads to ribosome pausing at their cognate codons in S. cerevisiae and C. elegans. Cells lacking U34 modifications exhibit gene expression hallmarks of proteotoxic stress and accumulate aggregates of endogenous proteins with key cellular functions. Moreover, these cells are severely compromised in clearing stress-induced protein aggregates. Restoration of codon-specific translation speed by tRNA overexpression is sufficient to reduce the cellular burden of protein aggregates, concomitantly relieving proteotoxic stress. Our findings thus establish modified U34 is an evolutionarily conserved accelerator of decoding and reveal a hitherto unappreciated role of tRNA anticodon modifications in maintaining proteome integrity.