ZMYND10 functions in a chaperone relay during axonemal dynein assembly

  1. Girish R Mali
  2. Patricia L Yeyati
  3. Seiya Mizuno
  4. Daniel O Dodd
  5. Peter A Tennant
  6. Margaret A Keighren
  7. Petra zur Lage
  8. Amelia Shoemark
  9. Amaya Garcia-Munoz
  10. Atsuko Shimada
  11. Hiroyuki Takeda
  12. Frank Edlich
  13. Satoru Takahashi
  14. Alex von Kreisheim
  15. Andrew Paul Jarman
  16. Pleasantine Mill  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. University of Tsukuba, Japan
  3. University of Dundee, United Kingdom
  4. University College Dublin, Ireland
  5. University of Tokyo, Japan
  6. University of Freiburg, Germany

Abstract

Molecular chaperones promote the folding and macromolecular assembly of a diverse set of 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets of substrates is unclear. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone that confers specificity for the FKBP8-HSP90 chaperone complex towards axonemal dynein clients required for cilia motility. Loss of ZMYND10 perturbs the chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. We show that pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with the loss of ZMYND10 in airway cells and that human disease-causing variants of ZMYND10 disrupt its ability to act as an FKBP8-HSP90 co-chaperone. Our study indicates that Primary Ciliary Dyskinesia (PCD), caused by mutations in dynein assembly factors disrupting cytoplasmic pre-assembly of axonemal dynein motors, should be considered a cell-type specific protein-misfolding disease.

Data availability

The mass spectrometry proteomics data have been deposited and is available on the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD006849.

The following data sets were generated

Article and author information

Author details

  1. Girish R Mali

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Patricia L Yeyati

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Seiya Mizuno

    Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel O Dodd

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter A Tennant

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Margaret A Keighren

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Petra zur Lage

    Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Amelia Shoemark

    Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Amaya Garcia-Munoz

    System Biology Ireland, University College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  10. Atsuko Shimada

    Department of Biological Sciences, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Hiroyuki Takeda

    Department of Biological Sciences, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Frank Edlich

    Institute for Biochemistry and Molecular Biology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Satoru Takahashi

    Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  14. Alex von Kreisheim

    Systems Biology Ireland, University College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  15. Andrew Paul Jarman

    Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4036-5701
  16. Pleasantine Mill

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Pleasantine.Mill@igmm.ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5218-134X

Funding

Medical Research Council (MRC_UU_12018/26)

  • Girish R Mali
  • Patricia L Yeyati
  • Daniel O Dodd
  • Peter A Tennant
  • Margaret A Keighren
  • Pleasantine Mill

Science Foundation Ireland

  • Amaya Garcia-Munoz
  • Alex von Kreisheim

Carnegie Trust for the Universities of Scotland

  • Girish R Mali
  • Andrew Paul Jarman
  • Pleasantine Mill

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

Ethics

Animal experimentation: All animal work was approved by a University of Edinburgh internal ethics committee and was performed in accordance with institutional guidelines under license by the UK Home Office (PPL 60/4424). Mice were maintained in an SPF environment in facilities of the University of Edinburgh (PEL 60/2605).

Reviewing Editor

  1. Jeremy F Reiter, University of California, San Francisco, United States

Publication history

  1. Received: December 15, 2017
  2. Accepted: June 18, 2018
  3. Accepted Manuscript published: June 19, 2018 (version 1)
  4. Version of Record published: July 13, 2018 (version 2)

Copyright

© 2018, Mali 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.

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  1. Girish R Mali
  2. Patricia L Yeyati
  3. Seiya Mizuno
  4. Daniel O Dodd
  5. Peter A Tennant
  6. Margaret A Keighren
  7. Petra zur Lage
  8. Amelia Shoemark
  9. Amaya Garcia-Munoz
  10. Atsuko Shimada
  11. Hiroyuki Takeda
  12. Frank Edlich
  13. Satoru Takahashi
  14. Alex von Kreisheim
  15. Andrew Paul Jarman
  16. Pleasantine Mill
(2018)
ZMYND10 functions in a chaperone relay during axonemal dynein assembly
eLife 7:e34389.
https://doi.org/10.7554/eLife.34389

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