Journal Article

The unfolded protein response affects readthrough of premature termination codons

Mann, Matthias, Oren, Yifat S, Geiger, Tamar, Rowe, Steven M, Rivlin, Joseph, Sorscher, Eric J, Zahdeh, Fouad, Bester, Assaf C, Manor, Miriam, Kerem, Eitan, Kerem, Batsheva, McClure, Michelle L

2014

Overview

One‐third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in‐frame PTCs enables synthesis of full‐length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter‐patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense‐mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD‐UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions. Synopsis Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described. Proteome analyses show substantial differences in unfolded protein response (UPR) activation between patients carrying PTCs, correlated with their response to readthrough treatment. UPR activation enables CFTR and XLF function following readthrough treatment. Proteome analyses uncover inverse correlation between UPR and nonsense‐mediated mRNA decay (NMD), suggesting a feedback‐loop mechanism between these homeostatic pathways. The NMD‐UPR feedback loop augments both UPR activation and NMD attenuation. The NMD‐UPR feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Graphical Abstract Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described.

• Publisher: Nature Publishing Group UK,EMBO Press,BlackWell Publishing Ltd,Springer Nature
• Subject: Cancer / Codon, Nonsense / Codons / Cystic fibrosis / EMBO16 / Experiments / Feedback / Gene expression / Gene Expression Regulation / Gene Regulatory Networks / Hereditary diseases / Homeostasis / Humans / mRNA turnover / Mutation / Nonsense Mediated mRNA Decay / Patients / Physiology / premature termination codon / Protein Biosynthesis / Protein folding / Proteins / Proteome - analysis / Proteomics / readthrough treatment / Research Article / Surveillance / Unfolded Protein Response