ZMYND10 functions in a chaperone relay during axonemal dynein assembly.

Autor:	Mali GR; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Yeyati PL; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Mizuno S; Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan., Dodd DO; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Tennant PA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Keighren MA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Zur Lage P; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Shoemark A; Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom., Garcia-Munoz A; Systems Biology Ireland, University College Dublin, Dublin, Ireland., Shimada A; Department of Biological Sciences, University of Tokyo, Tokyo, Japan., Takeda H; Department of Biological Sciences, University of Tokyo, Tokyo, Japan., Edlich F; Institute for Biochemistry and Molecular Biology, University of Freiburg, Freiburg, Germany.; BIOSS, Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany., Takahashi S; Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan.; Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan., von Kreigsheim A; Systems Biology Ireland, University College Dublin, Dublin, Ireland.; Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Jarman AP; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Mill P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Jun 19; Vol. 7. Date of Electronic Publication: 2018 Jun 19.
DOI:	10.7554/eLife.34389
Abstrakt:	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. Competing Interests: GM, PY, SM, DD, PT, MK, Pz, AS, AG, AS, HT, FE, ST, Av, AJ, PM No competing interests declared (© 2018, Mali et al.)
Databáze:	MEDLINE
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