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Free keywords:
MESSENGER-RNA DECAY; TRANSMEMBRANE CONDUCTANCE REGULATOR;
NONSENSE-MEDIATED DECAY; ENDOPLASMIC-RETICULUM STRESS; CYSTIC-FIBROSIS
PATIENTS; AMINOGLYCOSIDE ANTIBIOTICS; GENE-EXPRESSION; STOP MUTATIONS;
ESCHERICHIA-COLI; MAMMALIAN-CELLSnonsense-mediated mRNA decay; premature termination codon; readthrough
treatment; unfolded protein response;
Abstract:
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.
