Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Gustave Roussy Institute, Villejuif, France.
J Exp Med. 2019 Nov 4;216(11):2582-2601. doi: 10.1084/jem.20190008. Epub 2019 Aug 8.
Transendothelial migration (TEM) of leukocytes across the endothelium is critical for inflammation. In the endothelium, TEM requires the coordination of membrane movements and cytoskeletal interactions, including, prominently, recruitment of the lateral border recycling compartment (LBRC). The scaffold protein IQGAP1 was recently identified in a screen for LBRC-interacting proteins. Knockdown of endothelial IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. Expression of truncated IQGAP1 constructs demonstrated that the calponin homology domain is required for IQGAP1 localization to endothelial borders and that the IQ domain, on the same IQGAP1 polypeptide, is required for its function in TEM. This is the first reported function of IQGAP1 requiring two domains to be present on the same polypeptide. Additionally, we show for the first time that IQGAP1 in the endothelium is required for efficient TEM in vivo. These findings reveal a novel function for IQGAP1 and demonstrate that IQGAP1 in endothelial cells facilitates TEM by directing the LBRC to the site of TEM.
白细胞穿过内皮细胞的跨内皮迁移（TEM）对于炎症至关重要。在内皮细胞中，TEM 需要膜运动和细胞骨架相互作用的协调，包括突出的侧向边界再循环隔室（LBRC）的募集。支架蛋白 IQGAP1 最近在筛选与 LBRC 相互作用的蛋白质时被鉴定出来。内皮细胞 IQGAP1 的敲低破坏了 LBRC 的定向运动，并大大减少了白细胞 TEM。截断的 IQGAP1 构建体的表达表明，钙调蛋白同源结构域是 IQGAP1 定位于内皮边界所必需的，而 IQ 结构域（在同一 IQGAP1 多肽上）是其在 TEM 中发挥功能所必需的。这是首次报道 IQGAP1 需要两个结构域存在于同一多肽上的功能。此外，我们首次表明内皮细胞中的 IQGAP1 对于体内有效的 TEM 是必需的。这些发现揭示了 IQGAP1 的新功能，并表明内皮细胞中的 IQGAP1 通过将 LBRC 引导到 TEM 部位来促进 TEM。
