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 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 556 |
| DOIs | |
| Publication status | Published - 11 Apr 2018 |
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Keywords
- Animals
- Biological Evolution
- Cell Cycle Proteins/deficiency
- Cell Differentiation
- Cell Proliferation
- Disease Progression
- Epidermis/cytology
- Female
- Homeostasis/genetics
- Male
- Membrane Glycoproteins/metabolism
- Mice
- Microfilament Proteins/deficiency
- Mutation
- Nerve Tissue Proteins/metabolism
- Phenotype
- Protein Biosynthesis
- RNA, Messenger/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Ribosomes/metabolism
- Stem Cells/cytology
- TOR Serine-Threonine Kinases/antagonists & inhibitors
Cite this
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An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. / Liakath-Ali, Kifayathullah; Mills, Eric W.; Sequeira, Inês; Lichtenberger, Beate M.; Pisco, Angela Oliveira; Sipilä, Kalle H.; Mishra, Ajay; Yoshikawa, Harunori; Wu, Colin Chih-Chien; Ly, Tony; Lamond, Angus I.; Adham, Ibrahim M.; Green, Rachel; Watt, Fiona M. (Lead / Corresponding author).
In: Nature, Vol. 556, 11.04.2018, p. 376-380.Research output: Contribution to journal › Letter
TY - JOUR
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.
N1 - FMW gratefully acknowledges funding from the Wellcome Trust and UK Medical Research Council. We are also grateful for funding from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. RG acknowledges funding from Howard Hughes Medical Institute. TL is supported by Sir Henry Dale Fellowship (206211/Z/17/Z).
PY - 2018/4/11
Y1 - 2018/4/11
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.
KW - Animals
KW - Biological Evolution
KW - Cell Cycle Proteins/deficiency
KW - Cell Differentiation
KW - Cell Proliferation
KW - Disease Progression
KW - Epidermis/cytology
KW - Female
KW - Homeostasis/genetics
KW - Male
KW - Membrane Glycoproteins/metabolism
KW - Mice
KW - Microfilament Proteins/deficiency
KW - Mutation
KW - Nerve Tissue Proteins/metabolism
KW - Phenotype
KW - Protein Biosynthesis
KW - RNA, Messenger/metabolism
KW - Receptors, G-Protein-Coupled/metabolism
KW - Ribosomes/metabolism
KW - Stem Cells/cytology
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
U2 - 10.1038/s41586-018-0032-3
DO - 10.1038/s41586-018-0032-3
M3 - Letter
VL - 556
SP - 376
EP - 380
JO - Nature
JF - Nature
SN - 0028-0836
ER -