Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Curr Biol. 2020 May 4;30(9):1614-1625.e5. doi: 10.1016/j.cub.2020.02.028. Epub 2020 Mar 12.
Cells can sense and respond to various mechanical stimuli from their surrounding environment. One of the explanations for mechanosensitivity, a lipid-bilayer model, suggests that a stretch of the membrane induced by mechanical force alters the physical state of the lipid bilayer, driving mechanosensors to assume conformations better matched to the altered membrane. However, mechanosensors of this class are restricted to ion channels. Here, we reveal that integrin αIIbβ3, a prototypic adhesion receptor, can be activated by various mechanical stimuli including stretch, shear stress, and osmotic pressure. The force-induced integrin activation was not dependent on its known intracellular activation signaling events and was even observed in reconstituted cell-free liposomes. Instead, these mechanical stimuli were found to alter the lipid embedding of the integrin β3 transmembrane domain (TMD) and subsequently weaken the αIIb-β3 TMD interaction, which results in activation of the receptor. Moreover, artificial modulation of the membrane curvature near integrin αIIbβ3 can induce its activation in cells as well as in lipid nanodiscs, suggesting that physical deformation of the lipid bilayer, either by mechanical force or curvature, can induce integrin activation. Thus, our results establish the adhesion receptor as a bona fide mechanosensor that directly senses and responds to the force-modulated lipid environment. Furthermore, this study expands the lipid-bilayer model by suggesting that the force-induced topological change of TMDs and subsequent alteration in the TMD interactome is a molecular basis of sensing mechanical force transmitted via the lipid bilayer.
细胞可以感知和响应来自周围环境的各种机械刺激。机械敏感性的一种解释是脂质双层模型，它表明机械力引起的膜拉伸改变了脂质双层的物理状态，促使机械感受器采用更适合改变膜的构象。然而，这类机械感受器仅限于离子通道。在这里，我们揭示了整合素 αIIbβ3，一种典型的粘附受体，可以被各种机械刺激激活，包括拉伸、切应力和渗透压。力诱导的整合素激活不依赖于其已知的细胞内激活信号事件，甚至在重建的无细胞脂质体中也观察到。相反，这些机械刺激被发现改变了整合素 β3 跨膜域（TMD）的脂质嵌入，随后削弱了 αIIb-β3 TMD 相互作用，导致受体激活。此外，人工调节整合素 αIIbβ3 附近的膜曲率可以诱导其在细胞以及脂质纳米盘中的激活，这表明脂质双层的物理变形，无论是通过机械力还是曲率，都可以诱导整合素的激活。因此，我们的结果确立了粘附受体作为一种真正的机械感受器，它可以直接感知和响应力调制的脂质环境。此外，这项研究通过表明 TMD 拓扑结构的力诱导变化以及随后 TMD 相互作用组的改变是通过脂质双层传递的机械力的传感的分子基础，扩展了脂质双层模型。
