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Nature. 2018 Apr;556(7701):376-380. doi: 10.1038/s41586-018-0032-3. Epub 2018 Apr 11.

An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis.

Author information

1
Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
2
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA, USA.
3
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
4
Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
5
Cambridge Infinitus Research Centre, University of Cambridge, Cambridge, UK.
6
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK.
7
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
8
Institute of Human Genetics, University Medical Centre of Göttingen, Göttingen, Germany.
9
Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK. fiona.watt@kcl.ac.uk.

Abstract

Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation1,2. Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms3,4. One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes 5 . Here we show that Pelo is required for mammalian epidermal homeostasis. Conditional deletion of Pelo in mouse epidermal stem cells that express Lrig1 results in hyperproliferation and abnormal differentiation of these cells. By contrast, deletion of Pelo in Lgr5-expressing stem cells has no effect and deletion in Lgr6-expressing stem cells induces only a mild phenotype. Loss of Pelo results in accumulation of short ribosome footprints and global upregulation of translation, rather than affecting the expression of specific genes. Translational inhibition by rapamycin-mediated downregulation of mTOR (mechanistic target of rapamycin kinase) rescues the epidermal phenotype. Our study reveals that the ribosome-rescue machinery is important for mammalian tissue homeostasis and that it has specific effects on different stem cell populations.

PMID:
29643507
DOI:
10.1038/s41586-018-0032-3
[Indexed for MEDLINE]

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