Sharifkhodaei Zohreh, Padash-Barmchi Mojgan, Gilbert Mary M, Samarasekera Gayathri, Fulga Tudor A, Van Vactor David, Auld Vanessa J
Department of Zoology, University of British Columbia, Vancouver BC V6T 1Z3, Canada.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
J Cell Sci. 2016 Apr 1;129(7):1477-89. doi: 10.1242/jcs.178608. Epub 2016 Feb 16.
Epithelial bicellular and tricellular junctions are essential for establishing and maintaining permeability barriers. Tricellular junctions are formed by the convergence of three bicellular junctions at the corners of neighbouring epithelia. Gliotactin, a member of the Neuroligin family, is located at theDrosophilatricellular junction, and is crucial for the formation of tricellular and septate junctions, as well as permeability barrier function. Gliotactin protein levels are tightly controlled by phosphorylation at tyrosine residues and endocytosis. Blocking endocytosis or overexpressing Gliotactin results in the spread of Gliotactin from the tricellular junction, resulting in apoptosis, delamination and migration of epithelial cells. We show that Gliotactin levels are also regulated at the mRNA level by micro (mi)RNA-mediated degradation and that miRNAs are targeted to a short region in the 3'UTR that includes a conserved miR-184 target site. miR-184 also targets a suite of septate junction proteins, including NrxIV, coracle and Mcr. miR-184 expression is triggered when Gliotactin is overexpressed, leading to activation of the BMP signalling pathway. Gliotactin specifically interferes with Dad, an inhibitory SMAD, leading to activation of the Tkv type-I receptor and activation of Mad to elevate the biogenesis and expression of miR-184.
上皮双细胞和三细胞连接对于建立和维持通透性屏障至关重要。三细胞连接由相邻上皮细胞角处的三个双细胞连接汇聚形成。神经连接蛋白家族成员Gliotactin位于果蝇三细胞连接处,对三细胞连接和分隔连接的形成以及通透性屏障功能至关重要。Gliotactin蛋白水平通过酪氨酸残基的磷酸化和内吞作用受到严格控制。阻断内吞作用或过表达Gliotactin会导致Gliotactin从三细胞连接处扩散,从而导致上皮细胞凋亡、分层和迁移。我们发现,Gliotactin水平在mRNA水平上也受到微小(mi)RNA介导的降解调控,并且miRNA靶向3'UTR中的一个短区域,该区域包含一个保守的miR-184靶位点。miR-184还靶向一系列分隔连接蛋白,包括NrxIV、coracle和Mcr。当Gliotactin过表达时,miR-184表达被触发,导致BMP信号通路激活。Gliotactin特异性干扰抑制性SMAD蛋白Dad,导致Tkv I型受体激活以及Mad激活,从而提高miR-184的生物合成和表达。