Department of Medicine, University of California, San Diego, La Jolla, CA
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
J Cell Biol. 2018 Apr 2;217(4):1453-1465. doi: 10.1083/jcb.201707055. Epub 2018 Mar 13.
Integrin activation regulates adhesion, extracellular matrix assembly, and cell migration, thereby playing an indispensable role in development and in many pathological processes. A proline mutation in the central integrin β3 transmembrane domain (TMD) creates a flexible kink that uncouples the topology of the inner half of the TMD from the outer half. In this study, using leukocyte integrin α4β7, which enables development of gut-associated lymphoid tissue (GALT), we examined the biological effect of such a proline mutation and report that it impairs agonist-induced talin-mediated activation of integrin α4β7, thereby inhibiting rolling lymphocyte arrest, a key step in transmigration. Furthermore, the α4β7(L721P) mutation blocks lymphocyte homing to and development of the GALT. These studies show that impairing the ability of an integrin β TMD to transmit talin-induced TMD topology inhibits agonist-induced physiological integrin activation and biological function in development.
整合素激活调节黏附、细胞外基质组装和细胞迁移，从而在发育和许多病理过程中发挥不可或缺的作用。整合素β3 跨膜结构域（TMD）中心脯氨酸突变会产生一个灵活的弯曲，从而使 TMD 的内半部分与外半部分的拓扑结构解耦。在这项研究中，我们使用白细胞整合素 α4β7 来研究这种脯氨酸突变的生物学效应，该整合素使肠道相关淋巴组织（GALT）得以发育，我们报告称它会损害激动剂诱导的衔接蛋白介导的整合素 α4β7 激活，从而抑制淋巴细胞滚动捕获，这是迁移的关键步骤。此外，α4β7（L721P）突变会阻止淋巴细胞归巢到 GALT 并发育。这些研究表明，抑制整合素β TMD 传递衔接蛋白诱导的 TMD 拓扑的能力会抑制激动剂诱导的生理整合素激活和发育中的生物学功能。
