An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

Kifayathullah Liakath-Ali, Eric W. Mills, Inês Sequeira, Beate M. Lichtenberger, Angela Oliveira Pisco, Kalle H. Sipilä, Ajay Mishra, Harunori Yoshikawa, Colin Chih-Chien Wu, Tony Ly, Angus I. Lamond, Ibrahim M. Adham, Rachel Green and Fiona M. Watt ()
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Kifayathullah Liakath-Ali: King’s College London
Eric W. Mills: Johns Hopkins School of Medicine
Inês Sequeira: King’s College London
Beate M. Lichtenberger: King’s College London
Angela Oliveira Pisco: King’s College London
Kalle H. Sipilä: King’s College London
Ajay Mishra: King’s College London
Harunori Yoshikawa: University of Dundee
Colin Chih-Chien Wu: Johns Hopkins School of Medicine
Tony Ly: University of Dundee
Angus I. Lamond: University of Dundee
Ibrahim M. Adham: University Medical Centre of Göttingen
Rachel Green: Johns Hopkins School of Medicine
Fiona M. Watt: King’s College London

Nature, 2018, vol. 556, issue 7701, 376-380

Abstract: 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 ribosomes5. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0032-3

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