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).
Reviewing Editor
- Jeremy F Reiter, University of California, San Francisco, United States
Version history
- Received: December 15, 2017
- Accepted: June 18, 2018
- Accepted Manuscript published: June 19, 2018 (version 1)
- 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.
Metrics
-
- 2,836
- Page views
-
- 396
- Downloads
-
- 33
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
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)
ZMYND10 functions in a chaperone relay during axonemal dynein assembly
eLife 7:e34389.
https://doi.org/10.7554/eLife.34389
Further reading
-
- Cell Biology
- Physics of Living Systems
As cells migrate and experience forces from their surroundings, they constantly undergo mechanical deformations which reshape their plasma membrane (PM). To maintain homeostasis, cells need to detect and restore such changes, not only in terms of overall PM area and tension as previously described, but also in terms of local, nano-scale topography. Here we describe a novel phenomenon, by which cells sense and restore mechanically induced PM nano-scale deformations. We show that cell stretch and subsequent compression reshape the PM in a way that generates local membrane evaginations in the 100 nm scale. These evaginations are recognized by I-BAR proteins, which triggers a burst of actin polymerization mediated by Rac1 and Arp2/3. The actin polymerization burst subsequently re-flattens the evagination, completing the mechanochemical feedback loop. Our results demonstrate a new mechanosensing mechanism for PM shape homeostasis, with potential applicability in different physiological scenarios.
-
- Cell Biology
Epidemiological studies have demonstrated that fine particulate matter (PM2.5) is associated with adverse obstetric and postnatal metabolic health outcomes, but the mechanism remains unclear. This study aimed to investigate the toxicological pathways by which PM2.5 damaged placental trophoblasts in vivo and in vitro. We confirmed that PM2.5 induced adverse gestational outcomes such as increased fetal mortality rates, decreased fetal number and weight, damaged placental structure, and increased apoptosis of trophoblasts. Additionally, PM2.5 induced dysfunction of the trophoblast cell line HTR8/SVneo, including in its proliferation, apoptosis, invasion, migration and angiogenesis. Moreover, we comprehensively analyzed the transcriptional landscape of HTR8/SVneo cells exposed to PM2.5 through RNA-Seq and observed that PM2.5 triggered overexpression of pathways involved in oxidative stress and mitochondrial apoptosis to damage HTR8/SVneo cell biological functions through CYP1A1. Mechanistically, PM2.5 stimulated KLF9, a transcription factor identified as binding to CYP1A1 promoter region, which further modulated the CYP1A1-driven downstream phenotypes. Together, this study demonstrated that the KLF9/CYP1A1 axis played a crucial role in the toxic progression of PM2.5 induced adverse pregnancy outcomes, suggesting adverse effects of environmental pollution on pregnant females and putative targeted therapeutic strategies.
