ZMYND10 functions in a chaperone relay during axonemal dynein assembly

Girish R. Mali, Patricia L. Yeyati, Seiya Mizuno, Peter A. Tennant, Margaret A. Keighren, Petra zur Lage, Amelia Shoemark, Amaya Garcia-Munoz, Atsuko Shimada, Hiroyuki Takeda, Frank Edlich, Satoru Takahashi, Alexander von Kriegsheim, Andrew P. Jarman, Pleasantine Mill (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Article numbere34389
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume7
DOIs
Publication statusPublished - 19 Jun 2018

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Axonemal Dyneins
Dyneins
Proteostasis Deficiencies
Kartagener Syndrome
Molecular Chaperones
Cilia
Proteomics
Proteins
Pharmacology
Imaging techniques
Degradation
Mutation
Substrates

Cite this

Mali, G. R., Yeyati, P. L., Mizuno, S., Tennant, P. A., Keighren, M. A., Lage, P. Z., ... Mill, P. (2018). ZMYND10 functions in a chaperone relay during axonemal dynein assembly. eLife, 7, 1-27. [e34389]. https://doi.org/10.7554/eLife.34389
Mali, Girish R. ; Yeyati, Patricia L. ; Mizuno, Seiya ; Tennant, Peter A. ; Keighren, Margaret A. ; Lage, Petra zur ; Shoemark, Amelia ; Garcia-Munoz, Amaya ; Shimada, Atsuko ; Takeda, Hiroyuki ; Edlich, Frank ; Takahashi, Satoru ; von Kriegsheim, Alexander ; Jarman, Andrew P. ; Mill, Pleasantine. / ZMYND10 functions in a chaperone relay during axonemal dynein assembly. In: eLife. 2018 ; Vol. 7. pp. 1-27.
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Mali, GR, Yeyati, PL, Mizuno, S, Tennant, PA, Keighren, MA, Lage, PZ, Shoemark, A, Garcia-Munoz, A, Shimada, A, Takeda, H, Edlich, F, Takahashi, S, von Kriegsheim, A, Jarman, AP & Mill, P 2018, 'ZMYND10 functions in a chaperone relay during axonemal dynein assembly', eLife, vol. 7, e34389, pp. 1-27. https://doi.org/10.7554/eLife.34389

ZMYND10 functions in a chaperone relay during axonemal dynein assembly. / Mali, Girish R.; Yeyati, Patricia L.; Mizuno, Seiya; Tennant, Peter A.; Keighren, Margaret A.; Lage, Petra zur; Shoemark, Amelia; Garcia-Munoz, Amaya; Shimada, Atsuko; Takeda, Hiroyuki; Edlich, Frank; Takahashi, Satoru; von Kriegsheim, Alexander; Jarman, Andrew P.; Mill, Pleasantine (Lead / Corresponding author).

In: eLife, Vol. 7, e34389, 19.06.2018, p. 1-27.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ZMYND10 functions in a chaperone relay during axonemal dynein assembly

AU - Mali, Girish R.

AU - Yeyati, Patricia L.

AU - Mizuno, Seiya

AU - Tennant, Peter A.

AU - Keighren, Margaret A.

AU - Lage, Petra zur

AU - Shoemark, Amelia

AU - Garcia-Munoz, Amaya

AU - Shimada, Atsuko

AU - Takeda, Hiroyuki

AU - Edlich, Frank

AU - Takahashi, Satoru

AU - von Kriegsheim, Alexander

AU - Jarman, Andrew P.

AU - Mill, Pleasantine

PY - 2018/6/19

Y1 - 2018/6/19

N2 - 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.

AB - 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.

U2 - 10.7554/eLife.34389

DO - 10.7554/eLife.34389

M3 - Article

VL - 7

SP - 1

EP - 27

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e34389

ER -

Mali GR, Yeyati PL, Mizuno S, Tennant PA, Keighren MA, Lage PZ et al. ZMYND10 functions in a chaperone relay during axonemal dynein assembly. eLife. 2018 Jun 19;7:1-27. e34389. https://doi.org/10.7554/eLife.34389