Analysis of the 'angulin' proteins LSR, ILDR1 and ILDR2-tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis
Analysis of the 'angulin' proteins LSR, ILDR1 and ILDR2-tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis
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DOI：
10.1242/jcs.116442
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发表时间：
2013-02-15
影响因子：
4
通讯作者：
Furuse, Mikio
中科院分区：
文献类型：
--
作者：
Higashi, Tomohito;Tokuda, Shinsaku;Furuse, Mikio
三细胞紧密连接（tTJs）封闭了三细胞接触（TCs）的细胞外空间，即三个上皮细胞的角部相遇的地方。迄今为止，已知跨膜蛋白三胞蛋白和脂解刺激脂蛋白受体（LSR）是tTJs的分子成分。LSR向ttj招募三胞蛋白，这两种蛋白都是上皮细胞片完全屏障功能所必需的。在本研究中，我们发现两种lsr相关蛋白，免疫球蛋白样结构域受体（ILDR） 1和ILDR2也定位于TCs并招募三胞蛋白。LSR、ILDR1和ILDR2中至少有一种在小鼠的大多数上皮组织中表达。LSR、ILDR1和ILDR2的表达总体上是互补的，尽管LSR和ILDR1在一些上皮中共表达。当将ILDR1引入培养的上皮细胞时，ILDR1需要在上皮细胞中建立一个强大的屏障，类似于LSR，而ILDR2提供的屏障要弱得多。我们进一步分析了导致家族性耳聋的人类ILDR1突变DFNB42，发现大多数与DFNB42相关的ILDR1突变蛋白在募集三胞蛋白方面存在缺陷。我们还发现，与另一种家族性耳聋DFNB49相关的三胞蛋白突变蛋白没有被ILDR1招募到TCs中。这些发现表明ttj的分子组织在LSR、ILDR1或ILDR2含量方面存在异质性，并表明ILDR1介导的三胞蛋白向TCs的募集是听力所必需的。考虑到LSR、ILDR1和ILDR2在上皮细胞角部的共同定位和三胞蛋白的募集，我们建议将它们指定为角蛋白家族蛋白。
Tricellular tight junctions (tTJs) seal the extracellular space at tricellular contacts (TCs), where the corners of three epithelial cells meet. To date, the transmembrane proteins tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) are known to be molecular components of tTJs. LSR recruits tricellulin to tTJs, and both proteins are required for the full barrier function of epithelial cellular sheets. In the present study, we show that two LSR-related proteins, immunoglobulin-like domain-containing receptor (ILDR) 1 and ILDR2, are also localized at TCs and recruit tricellulin. At least one of LSR, ILDR1 and ILDR2 was expressed in most of the epithelial tissues in mice. The expressions of LSR, ILDR1 and ILDR2 were generally complementary to each other, although LSR and ILDR1 were co-expressed in some epithelia. ILDR1 was required for the establishment of a strong barrier of the epithelium, similar to LSR, when introduced into cultured epithelial cells, whereas ILDR2 provided a much weaker barrier. We further analyzed human ILDR1, mutations in which cause a familial deafness, DFNB42, and found that most DFNB42-associated ILDR1 mutant proteins were defective in recruitment of tricellulin. We also found that tricellulin mutant proteins associated with another familial deafness, DFNB49, were not recruited to TCs by ILDR1. These findings show the heterogeneity of the molecular organization of tTJs in terms of the content of LSR, ILDR1 or ILDR2, and suggest that ILDR1-mediated recruitment of tricellulin to TCs is required for hearing. Given their common localization at epithelial cell corners and recruitment of tricellulin, we propose to designate LSR, ILDR1 and ILDR2 as angulin family proteins.