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ZMYND10 functions in a chaperone relay during axonemal dynein assembly
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 t...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044906/ https://www.ncbi.nlm.nih.gov/pubmed/29916806 http://dx.doi.org/10.7554/eLife.34389 |
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author | Mali, Girish R Yeyati, Patricia L Mizuno, Seiya Dodd, Daniel O Tennant, Peter A Keighren, Margaret A zur Lage, Petra Shoemark, Amelia Garcia-Munoz, Amaya Shimada, Atsuko Takeda, Hiroyuki Edlich, Frank Takahashi, Satoru von Kreigsheim, Alex Jarman, Andrew P Mill, Pleasantine |
author_facet | Mali, Girish R Yeyati, Patricia L Mizuno, Seiya Dodd, Daniel O Tennant, Peter A Keighren, Margaret A zur Lage, Petra Shoemark, Amelia Garcia-Munoz, Amaya Shimada, Atsuko Takeda, Hiroyuki Edlich, Frank Takahashi, Satoru von Kreigsheim, Alex Jarman, Andrew P Mill, Pleasantine |
author_sort | Mali, Girish R |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6044906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-60449062018-07-16 ZMYND10 functions in a chaperone relay during axonemal dynein assembly Mali, Girish R Yeyati, Patricia L Mizuno, Seiya Dodd, Daniel O Tennant, Peter A Keighren, Margaret A zur Lage, Petra Shoemark, Amelia Garcia-Munoz, Amaya Shimada, Atsuko Takeda, Hiroyuki Edlich, Frank Takahashi, Satoru von Kreigsheim, Alex Jarman, Andrew P Mill, Pleasantine eLife Cell Biology 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. eLife Sciences Publications, Ltd 2018-06-19 /pmc/articles/PMC6044906/ /pubmed/29916806 http://dx.doi.org/10.7554/eLife.34389 Text en © 2018, Mali et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Mali, Girish R Yeyati, Patricia L Mizuno, Seiya Dodd, Daniel O Tennant, Peter A Keighren, Margaret A zur Lage, Petra Shoemark, Amelia Garcia-Munoz, Amaya Shimada, Atsuko Takeda, Hiroyuki Edlich, Frank Takahashi, Satoru von Kreigsheim, Alex Jarman, Andrew P Mill, Pleasantine ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title | ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title_full | ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title_fullStr | ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title_full_unstemmed | ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title_short | ZMYND10 functions in a chaperone relay during axonemal dynein assembly |
title_sort | zmynd10 functions in a chaperone relay during axonemal dynein assembly |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044906/ https://www.ncbi.nlm.nih.gov/pubmed/29916806 http://dx.doi.org/10.7554/eLife.34389 |
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