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Journal article
The unfolded protein response affects readthrough of premature termination codons
EMBO molecular medicine, Vol.6(5), pp.685-701
May/2014
PMCID: PMC4023889
PMID: 24705877
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.
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.
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.
Details
- Title
- The unfolded protein response affects readthrough of premature termination codons
- Creators
- Yifat S Oren - Hebrew University of JerusalemMichelle L McClure - University of Alabama at BirminghamSteven M Rowe - University of Alabama at BirminghamEric J Sorscher - University of Alabama at BirminghamAssaf C Bester - Hebrew University of JerusalemMiriam Manor - Hebrew University of JerusalemEitan Kerem - Hadassah Medical CenterJoseph Rivlin - Carmel Medical CenterFouad Zahdeh - Hebrew University of JerusalemMatthias Mann - Max Planck Institute of BiochemistryTamar Geiger - Tel Aviv UniversityBatsheva Kerem (Corresponding Author) - Hebrew University of Jerusalem
- Resource Type
- Journal article
- Publication Details
- EMBO molecular medicine, Vol.6(5), pp.685-701; May/2014
- Number of pages
- 17
- Language
- English
- DOI
- https://doi.org/10.1002/emmm.201303347
- PMID
- 24705877
- PMCID
- PMC4023889
- Grant note
- This study was partially supported by the Israeli Centers of Research Excellence (I-CORE), Gene Regulation in Complex Human Disease, Center No 41/11 to BK, grant from the Cystic Fibrosis Foundation to BK, the Legacy Heritage Bio-medical Program of the Israel Science Foundation (Grant No. 175/11) to BK, the Israel Ministry of Health (Grant No. 3000003038) to BK, the Israel Science Foundation (Grant No. 1617/12) to TG, NIH (P30 DK072482) to EJS, CFF (R464-CF) to EJS and ROWE13A0 to SMR. The authors wish to thank Maya Schuldiner for enlightening ideas and discussions, Sagiv Shifman for assistance in the statistical analyses, Orly Elpelg for the LPIN1 cells, Jean-Pierre de Villartay for the P133 cells, Yifat Eliezer, Maayan Roniger, and Efrat Ozeri-Galai for assistance with experiments. Author contributions: YSO designed and performed experiments, analyzed results, prepared the figures, and wrote the paper; MLM performed the SPQ experiments and analyzed their data, contributed to the paper preparation; SMR and EJS analyzed the SPQ data and contributed to the paper preparation; ACB analyzed the microarray data; MiM contributed to the RT-qPCR in some cell lines; EK assisted in collecting blood samples from CF patients for the proteomic analysis; JR assisted in getting the blood samples from the CF sister patients; FZ analyzed the NMD-triggering features; MaM contributed to the proteomic experiments performed on the CF sister patients and contributed to the paper preparation; TG designed and performed the proteomic experiments, analyzed their data, prepared their figures, and contributed to the paper preparation; BK designed research, analyzed and interpreted data, wrote the manuscript.
- Record Identifier
- 993286646303596
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