Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome.
Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome.
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DOI：
10.1038/s41598-018-30757-3
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发表时间：
2018-08-27
影响因子：
4.6
通讯作者：
Akiyama M
中科院分区：
文献类型：
--
作者：
Taki T;Takeichi T;Sugiura K;Akiyama M
编码连接蛋白 (Cx) 26 的 GJB2 种系错义突变已在角膜炎、鱼鳞病和耳聋 (KID) 综合征中被发现。我们探讨了与 KID 综合征致病人类突变体相对应的三种小鼠 Cx26 突变体（Cx26-G12R、-G45E 和 -D50N）对导致细胞死亡的半通道活性和免疫反应相关基因表达的影响。我们分析了表达野生型 (WT) 或突变型 Cx26 分子的细胞的 3D 图像，以清楚地证明 Cx26 突变体的细胞内定位和半通道形成。高细胞外 Ca2+ 条件导致 Cx26-G12R 或 Cx26-G45E 表达细胞中间隙连接半通道关闭，从而抑制 Cx26 突变体诱导的细胞死亡。荧光染料摄取测定显示，带有 Cx26-D50N 的细胞具有异常高的半通道活性，但半通道阻滞剂、甘草酸和 18α-甘草次酸可消除这种活性。这些结果进一步支持了异常半通道活动在 KID 综合征的发病机制中发挥重要作用的观点。此外，我们发现表达 Cx26-D50N 的角质形成细胞中 IL15、CCL5、IL1A、IL23R 和 TLR5 的表达下调，表明表达 Cx26-D50N 的 KID 综合征的免疫缺陷可能不仅与皮肤屏障缺陷有关，还与免疫反应相关基因的表达下调有关。
Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.
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DOI：
10.1038/jid.2008.335
发表时间：
2009-04
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Lee JR;Derosa AM;White TW
通讯作者：
White TW
影响因子：
3.6
作者：
Donnelly, Steven;English, Grant;Martin, Patricia E.
通讯作者：
Martin, Patricia E.
影响因子：
3.6
作者：
de Zwart-Storm, Eugene A.;Rosa, Rafael F. M.;van Steensel, Maurice A. M.
通讯作者：
van Steensel, Maurice A. M.
影响因子：
4.4
作者：
Ghilardi, N;Kljavin, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ
影响因子：
3.8
作者：
Ebihara, L;Steiner, E
通讯作者：
Steiner, E