A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

  1. Benjamin Albert
  2. Isabelle C Kos-Braun
  3. Anthony K Henras
  4. Christophe Dez
  5. Maria Paula Rueda
  6. Xu Zhang
  7. Olivier Gadal
  8. Martin Kos
  9. David Shore  Is a corresponding author
  1. University of Geneva, Switzerland
  2. Heidelberg University, Germany
  3. Université Paul Sabatier, France

Abstract

Ribosome biogenesis is a complex and energy-demanding process requiring tight coordination of ribosomal RNA (rRNA) and ribosomal protein (RP) production. Given the extremely high level of RP synthesis in rapidly growing cells, alteration of any step in the ribosome assembly process may impact growth by leading to proteotoxic stress. Although the transcription factor Hsf1 has emerged as a central regulator of proteostasis, how its activity is coordinated with ribosome biogenesis is unknown. Here we show that arrest of ribosome biogenesis in the budding yeast S. cerevisiae triggers rapid activation of a highly specific stress pathway that coordinately up-regulates Hsf1 target genes and down-regulates RP genes. Activation of Hsf1 target genes requires neo-synthesis of RPs, which accumulate in an insoluble fraction and presumably titrate a negative regulator of Hsf1, the Hsp70 chaperone. RP aggregation is also coincident with that of the RP gene activator Ifh1, a transcription factor that is rapidly released from RP gene promoters. Our data support a model in which the levels of newly-synthetized RPs, imported into the nucleus but not yet assembled into ribosomes, work to continuously balance Hsf1 and Ifh1 activity, thus guarding against proteotoxic stress during ribosome assembly.

Data availability

Sequencing data have been deposited in GEO under accession code GSE125226. Previously published data were used from Supplementary file 3 of Sung et al. 2016, eLife (https://elifesciences.org/articles/19105/figures#SD7-data) and Supplemental Table S3 from Sung et al. 2016, Mol Biol Cell (supp_E16-05-0290v1_mc-E16-05-0290-s06.xlsx).

The following data sets were generated

Article and author information

Author details

  1. Benjamin Albert

    Department of Molecular Biology, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Isabelle C Kos-Braun

    Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anthony K Henras

    Centre de Biologie Intégrative, Université Paul Sabatier, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Christophe Dez

    Centre de Biologie Intégrative, Université Paul Sabatier, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Maria Paula Rueda

    Department of Molecular Biology, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Xu Zhang

    Department of Molecular Biology, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Olivier Gadal

    Centre de Biologie Intégrative, Université Paul Sabatier, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9421-0831
  8. Martin Kos

    Biochemistry Centre (BZH), Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3337-9681
  9. David Shore

    Department of Molecular Biology, University of Geneva, Geneva, Switzerland
    For correspondence
    David.Shore@unige.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9859-143X

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_170153)

  • David Shore

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Version history

  1. Received: January 9, 2019
  2. Accepted: May 23, 2019
  3. Accepted Manuscript published: May 24, 2019 (version 1)
  4. Version of Record published: June 17, 2019 (version 2)

Copyright

© 2019, Albert et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 12,920
    views
  • 1,562
    downloads
  • 129
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Benjamin Albert
  2. Isabelle C Kos-Braun
  3. Anthony K Henras
  4. Christophe Dez
  5. Maria Paula Rueda
  6. Xu Zhang
  7. Olivier Gadal
  8. Martin Kos
  9. David Shore
(2019)
A ribosome assembly stress response regulates transcription to maintain proteome homeostasis
eLife 8:e45002.
https://doi.org/10.7554/eLife.45002

Share this article

https://doi.org/10.7554/eLife.45002

Further reading

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine
    Rajdeep Banerjee, Thomas J Meyer ... David D Roberts
    Research Article

    Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from Cd47−/− mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in Cd47−/− spleens but significantly depleted in Thbs1−/− spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119CD34+ progenitors and Ter119+CD34 committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in Thbs1−/− spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.

    1. Cell Biology
    Makiko Kashio, Sandra Derouiche ... Makoto Tominaga
    Research Article

    Reports indicate that an interaction between TRPV4 and anoctamin 1 (ANO1) could be widely involved in water efflux of exocrine glands, suggesting that the interaction could play a role in perspiration. In secretory cells of sweat glands present in mouse foot pads, TRPV4 clearly colocalized with cytokeratin 8, ANO1, and aquaporin-5 (AQP5). Mouse sweat glands showed TRPV4-dependent cytosolic Ca2+ increases that were inhibited by menthol. Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice and was inhibited by menthol both in wild-type and TRPM8KO mice. The basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor. Sweating could be important for maintaining friction forces in mouse foot pads, and this possibility is supported by the finding that wild-type mice climbed up a slippery slope more easily than TRPV4-deficient mice. Furthermore, TRPV4 expression was significantly higher in controls and normohidrotic skin from patients with acquired idiopathic generalized anhidrosis (AIGA) compared to anhidrotic skin from patients with AIGA. Collectively, TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targeted to develop agents that regulate perspiration.