ZMYND10 functions in a chaperone relay during axonemal dynein assembly.

Girish R Mali,Amaya Garcia-Munoz,Pleasantine Mill,Satoru Takahashi,Margaret A Keighren,Hiroyuki Takeda,Seiya Mizuno,Daniel O Dodd,Amelia Shoemark,Petra Zur Lage,Patricia L Yeyati,Frank Edlich,Peter A Tennant,Atsuko Shimada,Andrew P Jarman,Alex Von Kreigsheim

doi:10.7554/elife.34389

Abstract

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.

Highlights

Macromolecular motors of the dynein family power the essential beating of motile cilia/flagella.Motile cilia propel sperm cells, generate mucociliary clearance in airways, modulate nodal flow for embryonic left-right patterning and circulate cerebrospinal fluid inside the brain
We focused on a -7bp deletion mutant line (Zmynd[10] c.695_701 p.Met178Ilefs*183), which results in a frame shift with premature termination
Generation of a null allele was verified by ZMYND10 immunoblotting of testes extracts and immunofluorescence of multiciliated ependymal cells and lung cryosections (Figure 1B-D)

Summary

Introduction

Macromolecular motors of the dynein family power the essential beating of motile cilia/flagella. Motile cilia propel sperm cells, generate mucociliary clearance in airways, modulate nodal flow for embryonic left-right patterning and circulate cerebrospinal fluid inside the brain. Force-generating dynein motors are large molecular complexes visible by transmission electron microscopy (TEM), as ‘outer’ and ‘inner dynein arms’ (ODA, IDA) spaced at regular intervals along the microtubule axoneme. Each ODA motor consists of catalytic heavy chains (HC), intermediate chains (IC) and light chains (LC); IDAs have a more heterogeneous composition. At least 4 ODA and 7 IDA subtypes exist, each containing different HCs (Kollmar, 2016; Wickstead and Gull, 2007). Defective dyneins render cilia immotile, resulting in the severe congenital ciliopathy in humans termed

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