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

Dmitri Shcherbakov,Margarita Brilkova,Heithem Boukari,Endre Laczko,Harshitha Santhosh Kumar,Hubert Rehrauer,Adrian Cortes-Sanchon,Youjin Teo,Reda Juskeviciene,Erik C Böttger,Rashid Akbergenov,Stefan Duscha,Ivan Osinnii,Matilde Mantovani,Eric Westhof,James Moore

doi:10.1038/s42003-019-0626-9

Abstract

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.

Highlights

Translation fidelity is the limiting factor in the accuracy of gene expression
By aligning the RPS2 sequences of S. cerevisiae and Homo sapiens, we identified A226Y as the homologous human RPS2 mutation, corresponding
Cell viability was not measurably affected in the RPS2-A226Y mutants (Fig. 1b), we detected a significantly longer generation time compared to RPS2 wt transfected cells (Fig. 1c)

Summary

Introduction

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. The average error rate in mRNA decoding by the ribosome has been estimated to be in the order of 10–4, making it the limiting factor in the accuracy of gene expression[2,3]. In higher eukaryotes reported defects in translational accuracy have mostly been linked to mutations which affect ribosomal accuracy in a non-random manner, i.e., mutations in specific aminoacyl-tRNA synthetases. These mutations come along with severe disease pathologies[11,12,13,14,15]. When the balance of protein homeostasis is disrupted, transcriptional programs dedicated to specific cellular compartments such as the cytosolic stress response and the unfolded protein response (UPR) pathways are activated in addition to the ubiquitinproteasome pathway and autophagy to aid refolding of misfolded proteins and to remove terminally misfolded and aggregated proteins[17,18,19]

Methods

Results

Conclusion