The unfolded protein response affects readthrough of premature termination codons

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageAmerican English
Pages (from-to)685-701
Number of pages17
JournalEMBO Molecular Medicine
Volume6
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Nonsense-mediated mRNA decay
  • Premature termination codon
  • Readthrough treatment
  • Unfolded protein response

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