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; Fiona M Watt

doi:10.1038/s41586-018-0032-3

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, Fiona M Watt

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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.

Original language	English
Pages (from-to)	376–380
Journal	Nature
Volume	556
Early online date	11 Apr 2018
DOIs	https://doi.org/10.1038/s41586-018-0032-3
Publication status	Published - 19 Apr 2018

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An evolutionarily conserved_LIAKATH-ALI_Publishedonline11April2018_GREEN AAMAccepted author manuscript, 9.86 MB

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title = "An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis",

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.",

author = "Kifayathullah Liakath-Ali and Mills, {Eric W} and In{\^e}s Sequeira and Lichtenberger, {Beate M} and Pisco, {Angela Oliveira} and Sipil{\"a}, {Kalle H} and Ajay Mishra and Harunori Yoshikawa and Wu, {Colin Chih-Chien} and Tony Ly and Lamond, {Angus I} and Adham, {Ibrahim M} and Rachel Green and Watt, {Fiona M}",

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doi = "10.1038/s41586-018-0032-3",

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T1 - An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

AU - Liakath-Ali, Kifayathullah

AU - Mills, Eric W

AU - Sequeira, Inês

AU - Lichtenberger, Beate M

AU - Pisco, Angela Oliveira

AU - Sipilä, Kalle H

AU - Mishra, Ajay

AU - Yoshikawa, Harunori

AU - Wu, Colin Chih-Chien

AU - Ly, Tony

AU - Lamond, Angus I

AU - Adham, Ibrahim M

AU - Green, Rachel

AU - Watt, Fiona M

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-018-0032-3

DO - 10.1038/s41586-018-0032-3

M3 - Letter

C2 - 29643507

SN - 0028-0836

VL - 556

SP - 376

EP - 380

JO - Nature

JF - Nature

ER -

An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

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