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NEK10在呼吸道粘膜纤毛清除中的基本功能
2020-01-25 10:48

美国麻省总医院Raghu R. Chivukula、沙特阿拉伯费萨尔国王专科医院和研究中心Fowzan S. Alkuraya等研究人员合作揭示,人类纤毛病中NEK10在呼吸道粘膜纤毛清除中的基本功能。该项研究成果2020年1月20日在线发表在《自然—医学》上。

研究人员确定了由突变导致的支气管扩张综合症,该突变使NIMA相关激酶10(NEK10)失活,这是哺乳动物体内功能未知的蛋白激酶。经过基因改造的人类原代呼吸道培养物将NEK10建立为纤毛细胞特异性激酶,其活性调节活动性纤毛蛋白质组以促进纤毛长度和粘液纤毛运输,但对于正常纤毛数、放射状结构和搏动频率是必不可少的。这些数据共同确定了一种新颖且可能是可靶向的信号轴,其可控制人类的运动性纤毛功能,并对以粘膜纤毛清除力受损为特征的其他呼吸系统疾病具有潜在影响。

据研究人员介绍,粘液纤毛清除是哺乳动物引导呼吸道将病原体和有害表面物质从呼吸道排出的生理过程,取决于多种专门细胞的协调功能,包括基底干细胞、分泌粘液的杯状细胞、活动性纤毛细胞、囊性纤维化富含跨膜电导调节蛋白(CFTR)的离子细胞和免疫细胞。支气管扩张是一种病理性的呼吸道扩张综合征,伴有粘膜纤毛清除功能受损,可能偶尔发生或由于孟德尔遗传病而发生,例如在囊性纤维化、原发性睫状运动障碍(PCD)和某些免疫缺陷中。先前的研究已经确定了影响PCD中纤毛结构和聚集的突变,但对粘膜纤毛转运的调控仍未完全了解,并且缺乏对其调节的治疗靶标。

附:英文原文

Title: A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance

Author: Raghu R. Chivukula, Daniel T. Montoro, Hui Min Leung, Jason Yang, Hanan E. Shamseldin, Martin S. Taylor, Gerard W. Dougherty, Maimoona A. Zariwala, Johnny Carson, M. Leigh Anne Daniels, Patrick R. Sears, Katharine E. Black, Lida P. Hariri, Ibrahim Almogarri, Evgeni M. Frenkel, Vladimir Vinarsky, Heymut Omran, Michael R. Knowles, Guillermo J. Tearney, Fowzan S. Alkuraya, David M. Sabatini

Issue&Volume: 2020-01-20

Abstract: Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.

DOI: 10.1038/s41591-019-0730-x

Source: https://www.nature.com/articles/s41591-019-0730-x

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:87.241
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex


本期文章:《自然—医学》:Online/在线发表

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