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Nat Cell Biol. 2017 Feb;19(2):94-105. doi: 10.1038/ncb3461. Epub 2017 Jan 16.

Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress.

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Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, 08028 Barcelona, Spain.
CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain.
IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain.
CIBER of Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.


The cytoplasmic polyadenylation element-binding (CPEB) proteins regulate pre-mRNA processing and translation of CPE-containing mRNAs in early embryonic development and synaptic activity. However, specific functions in adult organisms are poorly understood. Here we show that CPEB4 is required for adaptation to high-fat-diet- and ageing-induced endoplasmic reticulum (ER) stress, and subsequent hepatosteatosis. Stress-activated liver CPEB4 expression is dual-mode regulated. First, Cpeb4 mRNA transcription is controlled by the circadian clock, and then its translation is regulated by the unfolded protein response (UPR) through upstream open reading frames within the 5'UTR. Thus, the CPEB4 protein is synthesized only following ER stress but the induction amplitude is circadian. In turn, CPEB4 activates a second wave of UPR translation required to maintain ER and mitochondrial homeostasis. Our results suggest that combined transcriptional and translational Cpeb4 regulation generates a 'circadian mediator', which coordinates hepatic UPR activity with periods of high ER-protein-folding demand. Accordingly, CPEB4 deficiency results in non-alcoholic fatty liver disease.

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