Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11531-11540. doi: 10.1073/pnas.1918462117. Epub 2020 May 15.
A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using the follicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein-protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.
极化结构是上皮结构和功能的核心。在许多细胞中，极性涉及 Par 复合物和 Scribble（Scrib）模块之间的相互拮抗。虽然 Par 介导的顶端决定的分子机制已经很清楚，但 Scrib 模块蛋白如何指定基底外侧域仍然未知。在这里，我们使用滤泡上皮来证明 Scrib、Discs-large (Dlg) 和 Lethal giant larvae (Lgl) 的依赖和独立活性。我们的数据支持定位的线性层次结构，但排除了以前提出的蛋白质-蛋白质相互作用对于极化的必要性。Scrib 的皮质募集不需要棕榈酰化或极性磷脂结合，但Dlg 的独立皮质稳定活性确实如此。Scrib 和 Dlg 并不直接拮抗非典型蛋白激酶 C（aPKC），但它们可能通过使 Lgl 具有抑制 aPKC 的活性来限制 aPKC 的定位。重要的是，虽然 Scrib、Dlg 和 Lgl 都是必需的，但它们三者一起不足以拮抗 Par 复合物。我们的数据证明了 Scrib 模块中以前未被认识到的功能多样性，并开始定义 Scrib 和 Dlg 难以捉摸的分子功能。
