New Protein Variants Resulting from RNA Editing May Lead to Proteotoxic Stress

Abstract

Maintaining protein homeostasis is critical for cellular function, as disruptions can result in accumulation of misfolded proteins associated with various diseases. RNA editing, particularly deamination by base-editing enzymes like ADAR, can modify the transcriptome, potentially influencing amino acid sequences and protein diversity. We hypothesize that irregular RNA editing, leading to a more complex proteome, may generate defective proteins, triggering cellular toxicity. Using an editing-naïve yeast system expressing a robust ADAR enzyme, we demonstrated that extensive RNA editing results in non-synonymous protein changes, correlated with increased protein ubiquitination and reliance on quality control pathways. This suggests that extensive editing in yeast produces abnormal proteins prone to misfolding and degradation. While mouse and human genomes are well-adapted to the ADAR enzymes, introduction of base editors into human cells is found to increase activity in proteotoxic-stress-related pathways due to off-target editing. Signs of proteotoxic stress are also observed in human samples exhibiting elevated activity of endogenous ADARs. These findings emphasize the detrimental impact of dysregulated RNA editing on protein balance and suggest a potential role for aberrant editing in disease onset and progression.