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Deficiency in mTORC 1‐controlled C/ EBP β ‐ mRNA translation improves metabolic health in mice
Author(s) -
Zidek Laura M,
Ackermann Tobias,
Hartleben Götz,
Eichwald Sabrina,
Kortman Gertrud,
Kiehntopf Michael,
Leutz Achim,
Sonenberg Nahum,
Wang ZhaoQi,
Maltzahn Julia,
Müller Christine,
Calkhoven Cornelis F
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201439837
Subject(s) - mtorc1 , translation (biology) , p70 s6 kinase 1 , biology , messenger rna , regulator , microbiology and biotechnology , eif4a , calorie restriction , integrated stress response , upstream open reading frame , ribosomal protein s6 , open reading frame , biochemistry , signal transduction , gene , pi3k/akt/mtor pathway , endocrinology , peptide sequence
The mammalian target of rapamycin complex 1 ( mTORC 1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC 1 signalling are the mRNA translation regulators p70 ribosomal protein S6 kinase 1 (S6K1p70) and the 4E‐binding proteins (4E‐ BP s). However, little is known about vertebrate mRNA s that are specifically controlled by mTORC 1 signalling and are engaged in regulating mTORC 1‐associated physiology. Here, we show that translation of the CCAAT /enhancer binding protein beta ( C/ EBP β ) mRNA into the C/ EBP β‐ LIP isoform is suppressed in response to mTORC 1 inhibition either through pharmacological treatment or through calorie restriction. Our data indicate that the function of 4E‐ BP s is required for suppression of LIP . Intriguingly, mice lacking the cis ‐regulatory upstream open reading frame ( uORF ) in the C/ EBP β ‐ mRNA , which is required for mTORC 1‐stimulated translation into C/ EBP β‐ LIP , display an improved metabolic phenotype with features also found under calorie restriction. Thus, our data suggest that translational adjustment of C/ EBP β‐isoform expression is one of the key processes that direct metabolic adaptation in response to changes in mTORC 1 activity.