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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
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.
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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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