Open AccessThe unfolded protein response affects readthrough of premature termination codons
Author(s) -
Oren Yifat S,
McClure Michelle L,
Rowe Steven M,
Sorscher Eric J,
Bester Assaf C,
Manor Miriam,
Kerem Eitan,
Rivlin Joseph,
Zahdeh Fouad,
Mann Matthias,
Geiger Tamar,
Kerem Batsheva
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303347
Subject(s) - nonsense mediated decay , unfolded protein response , biology , microbiology and biotechnology , homeostasis , integrated stress response , genetics , gene , messenger rna , translation (biology) , rna , rna splicing
One‐third of monogenic inherited diseases result from premature termination codons ( PTC s). Readthrough of in‐frame PTC s 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 PTC s. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTC s, 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 PTC s and for cell homeostasis under normal conditions.