Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress
Knoerlein, A.; Nishikawa, K.; Kitamura, N.; Kumari, R.; Murakami, S.; Shrivastava, A.; Doynova, M.; Ciobu, N.; Walker, N.; Mei, X.; Dozic, A. V.; Rahman, J.; Xiao, Y.; Evans, C.; Yang, X.; Kharas, M. G.; Abdel-Wahab, O.; Fuks, F.; Singh, K.; Jaffrey, S.; Sanghvi, V. R.; Galligan, J. J.; David, Y.
Show abstract
Non-enzymatic RNA modifications expand the epitranscriptome, encoding a rapid and chemistry-driven response to cellular stress. While methylglyoxal, a reactive glycolytic byproduct of metabolic stress, has been shown to modify proteins and DNA, its impact on RNA has remained unexplored. Here, we identify mRNA as a dynamic substrate of MGO, whose modification is actively regulated by DJ-1 and the glyoxalase detoxification system. We show that mRNA glycation impairs translation and engages both the integrated stress response and the ribotoxic stress pathway, culminating in compromised pancreatic {beta}-cell function and reduced insulin secretion. Notably, this phenotype is alleviated by the frontline antihyperglycemic agent metformin. Together, our findings position mRNA as a direct sensor of metabolic stress and establish RNA glycation as a mechanistic link between glycolytic imbalance, translational stress and disease.
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