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 (Lead / Corresponding author)

Research output: Contribution to journalLetter

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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 languageEnglish
Pages (from-to)376-380
Number of pages5
JournalNature
Volume556
DOIs
Publication statusPublished - 11 Apr 2018

Fingerprint

Ribosomes
Homeostasis
Stem Cells
Sirolimus
Quality Control
Phenotype
Eukaryota
Cell Differentiation
Phosphotransferases
Up-Regulation
Down-Regulation
Yeasts
Gene Expression
Messenger RNA
Population
Proteins

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

Liakath-Ali, K., Mills, E. W., Sequeira, I., Lichtenberger, B. M., Pisco, A. O., Sipilä, K. H., ... Watt, F. M. (2018). An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. Nature, 556, 376-380. https://doi.org/10.1038/s41586-018-0032-3
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. / An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. In: Nature. 2018 ; Vol. 556. pp. 376-380.
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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.",
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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.}",
note = "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).",
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Liakath-Ali, K, Mills, EW, Sequeira, I, Lichtenberger, BM, Pisco, AO, Sipilä, KH, Mishra, A, Yoshikawa, H, Wu, CC-C, Ly, T, Lamond, AI, Adham, IM, Green, R & Watt, FM 2018, 'An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis', Nature, vol. 556, pp. 376-380. https://doi.org/10.1038/s41586-018-0032-3

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 journalLetter

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

C2 - 29643507

VL - 556

SP - 376

EP - 380

JO - Nature

JF - Nature

SN - 0028-0836

ER -

Liakath-Ali K, Mills EW, Sequeira I, Lichtenberger BM, Pisco AO, Sipilä KH et al. An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. Nature. 2018 Apr 11;556:376-380. https://doi.org/10.1038/s41586-018-0032-3