Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10-4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

This study describes the metabolomic analysis of HEK293 cells lines expressing mutant ribosomal protein RPS2 (human A226Y). RPS2 A226Y mutation has been shown to cause misreading and readthrough. Results provide insight into the response to chronic mistranslation in mammalian cells.