MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Seiya Mizuno
Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan
Daniel O Dodd
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Peter A Tennant
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Margaret A Keighren
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Petra zur Lage
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
Amelia Shoemark
Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
Amaya Garcia-Munoz
Systems Biology Ireland, University College Dublin, Dublin, Ireland
Atsuko Shimada
Department of Biological Sciences, University of Tokyo, Tokyo, Japan
Hiroyuki Takeda
Department of Biological Sciences, University of Tokyo, Tokyo, Japan
Frank Edlich
Institute for Biochemistry and Molecular Biology, University of Freiburg, Freiburg, Germany; BIOSS, Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
Satoru Takahashi
Laboratory Animal Resource Centre, University of Tsukuba, Tsukuba, Japan; Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
Alex von Kreigsheim
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
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.
