ZMYND10 functions in a chaperone relay during axonemal dynein assembly.
ZMYND10 functions in a chaperone relay during axonemal dynein assembly.
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作者：
Mali GR;Yeyati PL;Mizuno S;Dodd DO;Tennant PA;Keighren MA;Zur Lage P;Shoemark A;Garcia-Munoz A;Shimada A;Takeda H;Edlich F;Takahashi S;von Kreigsheim A;Jarman AP;Mill P
分子伴侣促进一组不同的“客户”蛋白质的折叠和大分子组装。无处不在的伴侣机制如何将其活动导向特定的底物集尚不清楚。通过使用小鼠遗传学、成像和定量蛋白质组学，我们发现ZMYND 10是一种新型的共分子伴侣，其赋予FKBP 8-HSP 90分子伴侣复合物对纤毛运动所需的轴丝动力蛋白客户的特异性。ZMYND 10的缺失扰乱了轴丝动力蛋白重链的伴侣作用，引发动力蛋白运动亚基的更广泛降解。我们表明，药理学抑制FKBP 8表型模仿动力蛋白运动不稳定性与气道细胞中ZMYND 10的丢失相关，并且ZMYND 10的人类致病变体破坏其作为FKBP 8-HSP 90共伴侣的能力。我们的研究表明，原发性纤毛运动障碍（PCD），在动力蛋白组装因子的突变破坏轴丝动力蛋白马达的细胞质预组装引起的，应被认为是一种细胞类型特异性蛋白质错误折叠疾病。
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.
DOI：
10.1083/jcb.62.3.899
发表时间：
1974-09
期刊：
The Journal of cell biology
影响因子：
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作者：
Dirksen ER
通讯作者：
Dirksen ER