CDHR3 Asthma-Risk Genotype Affects Susceptibility of Airway Epithelium to Rhinovirus C Infections
CDHR3 Asthma-Risk Genotype Affects Susceptibility of Airway Epithelium to Rhinovirus C Infections
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DOI：
10.1165/rcmb.2018-0220oc
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Gern, James E.
中科院分区：
文献类型：
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作者：
Basnet, Sarmila;Bochkov, Yury A.;Gern, James E.
CDHR3(钙粘素相关家族成员3)是一种在呼吸道上皮细胞中高表达的跨膜蛋白，是已知的唯一鼻病毒C受体。带有G到A碱基改变的CDHR3 SNP(Rs6967330)与哮喘的严重恶化和幼儿对RV-C感染的易感性增加有关。本研究的目的是确定CDHR3的亚细胞定位，并验证CDHR3哮喘易感基因影响呼吸道上皮细胞功能和对RV-C感染易感性的假设。我们使用免疫荧光成像、Western印迹分析和透射电子显微镜显示CDHR3在心尖细胞中的亚细胞定位，包括在呼吸道上皮细胞纤毛中的表达。CDHR3 rs6967330基因座(G->；A)的多态与CDHR3表达和上皮细胞功能的差异有关。与rs6967330 G等位基因相比，rs6967330 A等位基因具有更高的总蛋白表达和RV-C结合及复制能力。此外，rs6967330 A等位基因与纤毛发生早和FOXJ1高表达相关。CDHR3基因对膜完整性和纤毛搏动功能无显著影响。这些发现提供了有关CDHR3在呼吸道中的亚细胞定位和可能功能的信息，并将CDHR3哮喘风险基因与RV-C结合和复制增加联系起来。
CDHR3 (cadherin-related family member 3) is a transmembrane protein that is highly expressed in airway epithelia and the only known receptor for rhinovirus C (RV-C). A CDHR3 SNP (rs6967330) with G to A base change has been linked to severe exacerbations of asthma and increased susceptibility to RV-C infections in young children. The goals of this study were to determine the subcellular localization of CDHR3 and to test the hypothesis that CDHR3 asthma-risk genotype affects epithelial cell function and susceptibility to RV-C infections of the airway epithelia. We used immunofluorescence imaging, Western blot analysis, and transmission electron microscopy to show CDHR3 subcellular localization in apical cells, including expression in the cilia of airway epithelia. Polymorphisms in CDHR3 rs6967330 locus (G -> A) that were previously associated with childhood asthma were related to differences in CDHR3 expression and epithelial cell function. The rs6967330 A allele was associated with higher overall protein expression and RV-C binding and replication compared with the rs6967330 G allele. Furthermore, the rs6967330 A allele was associated with earlier ciliogenesis and higher FOXJ1 expression. Finally, CDHR3 genotype had no significant effects on membrane integrity or ciliary beat function. These findings provide information on the subcellular localization and possible functions of CDHR3 in the airways and link CDHR3 asthma-risk genotype to increased RV-C binding and replication.