ZMYND10 functions in a chaperone relay during axonemal dynein assembly
- University of Edinburgh, United Kingdom
- University of Tsukuba, Japan
- University of Dundee, United Kingdom
- University College Dublin, Ireland
- University of Tokyo, Japan
- 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.
Article and author information
Author details
Andrew Paul Jarman
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).
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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ZMYND10 functions in a chaperone relay during axonemal dynein assembly
eLife 7:e34389.
https://doi.org/10.7554/eLife.34389
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