An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis.

Autor: Liakath-Ali K; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.; Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA, USA., Mills EW; Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA., Sequeira I; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK., Lichtenberger BM; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.; Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria., Pisco AO; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK., Sipilä KH; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK., Mishra A; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.; Cambridge Infinitus Research Centre, University of Cambridge, Cambridge, UK., Yoshikawa H; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK., Wu CC; Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA., Ly T; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK.; Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Lamond AI; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK., Adham IM; Institute of Human Genetics, University Medical Centre of Göttingen, Göttingen, Germany., Green R; Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA., Watt FM; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK. fiona.watt@kcl.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 Apr; Vol. 556 (7701), pp. 376-380. Date of Electronic Publication: 2018 Apr 11.
DOI: 10.1038/s41586-018-0032-3
Abstrakt: Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation 1,2 . 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 mechanisms 3,4 . 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.
Databáze: MEDLINE
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