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ZMYND10 functions in a chaperone relay during axonemal dynein assembly.

Mali G.R., Yeyati P.L., Mizuno S., Dodd D.O., Tennant P.A., Keighren M.A., Zur Lage P., Shoemark A., Garcia-Munoz A., Shimada A., Takeda H., Edlich F., Takahashi S., von Kreigsheim A., Jarman A.P., Mill P.

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 7:0-0(2018) [PubMed] [Europe PMC]

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