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ZMYND10 functions in a chaperone relay during axonemal dynein assembly

By Girish R. Mali, Patricia L Yeyati, Seiya Mizuno, Margaret A Keighren, Petra zur Lage, Amaya Garcia-Munoz, Atsuko Shimada, Hiroyuki Takeda, Frank Edlich, Satoru Takahashi, Alex von Kriegsheim, Andrew Paul Jarman, Pleasantine Mill

Posted 13 Dec 2017
bioRxiv DOI: 10.1101/233718 (published DOI: 10.7554/elife.34389)

Molecular chaperones promote the folding and macromolecular assembly of a diverse set of substrate 'client' proteins. How the ubiquitous chaperone machinery directs its activities towards a specific set of substrates and whether this selectivity could be targeted for therapeutic intervention is of intense research. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone for the FKBP8-HSP90 chaperone complex during the biosynthesis of axonemal dynein heavy chains required for cilia motility. In the absence of ZMYND10, defects in dynein heavy chains trigger broader dynein motor degradation. We show that FKBP8 inhibition phenocopies dynein motor instability in airway cells, and human disease-causing variants of ZMYND10 disrupt its ability to act as FKBP8-HSP90 co-chaperone. Our study indicates that the motile ciliopathy Primary Ciliary Dyskinesia (PCD) should be considered a cell-type specific protein-misfolding disease and opens the potential for rational drug design that could restore specificity to the ubiquitous chaperone apparatus towards dynein subunits.

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