ZMYND10 functions in a chaperone relay during axonemal dynein assembly
ZMYND10 functions in a chaperone relay during axonemal dynein assembly
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DOI：
10.1101/233718
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发表时间：
2017-12
期刊：
影响因子：
7.7
通讯作者：
G. Mali;P. Yeyati;S. Mizuno;M. Keighren;P. zur Lage;A. García-Muñoz;A. Shimada;H. Takeda;F. Edlich;Satoru Takahashi;A. von Kriegsheim;A. Jarman;P. Mill
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文献类型：
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作者：
G. Mali;P. Yeyati;S. Mizuno;M. Keighren;P. zur Lage;A. García-Muñoz;A. Shimada;H. Takeda;F. Edlich;Satoru Takahashi;A. von Kriegsheim;A. Jarman;P. Mill
分子伴侣促进多种底物“客户”蛋白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一组特定的底物，以及这种选择性是否可以作为治疗干预的目标，目前正在进行激烈的研究。通过小鼠遗传学、影像学和定量蛋白质组学，我们发现ZMYND10在纤毛运动所需的轴突动力蛋白重链的生物合成过程中是FKBP8-HSP90伴侣复合物的一种新的共同伴侣。在缺乏ZMYND10的情况下，动力蛋白重链中的缺陷会引发更广泛的动力蛋白运动降解。我们发现，FKBP8抑制表型会影响气道细胞中的动力蛋白运动不稳定性，而ZMYND10的人类致病变体会破坏其作为FKBP8- hsp90共同伴侣的能力。我们的研究表明，运动性纤毛病原发性纤毛运动障碍（PCD）应被视为一种细胞型特异性蛋白质错误折叠疾病，并为合理的药物设计打开了可能性，可以恢复无处不在的伴侣体对动力蛋白亚基的特异性。
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.