Hase Koji, Kimura Shunsuke, Takatsu Hiroyuki, Ohmae Masumi, Kawano Sayaka, Kitamura Hiroshi, Ito Masatoshi, Watarai Hiroshi, Hazelett C Clayton, Yeaman Charles, Ohno Hiroshi
Laboratory for Epithelial Immunobiology, Kanagawa 230-0045, Japan.
Nat Cell Biol. 2009 Dec;11(12):1427-32. doi: 10.1038/ncb1990. Epub 2009 Nov 22.
Cell-cell communication is essential for the development and homeostasis of multicellular organisms. Recently, a new type of cell-cell communication was discovered that is based on the formation of thin membranous nanotubes between remote cells. These long membrane tethers, termed tunneling nanotubes (TNTs), form an intercellular conduit and have been shown to enable the transport of various cellular components and signals. However, the molecular basis for TNT formation remains to be elucidated. Here we report that a mammalian protein, M-Sec, induces de novo formation of numerous membrane protrusions extending from the plasma membrane, some of which tether onto adjacent cells and subsequently form TNT-like structures. Depletion of M-Sec by RNA interference (RNAi) greatly reduced endogenous TNT formation as well as intercellular propagation of a calcium flux in a macrophage cell line. Furthermore, blockage of the interaction of M-Sec with Ral and the exocyst complex, which serves as a downstream effector of Ral, attenuated the formation of membrane nanotubes. Our results reveal that M-Sec functions as a key regulator of membrane nanotube formation through interaction with the Ral-exocyst pathway.
细胞间通讯对于多细胞生物体的发育和内环境稳定至关重要。最近，发现了一种新型的细胞间通讯方式，它基于远端细胞之间形成的薄的膜性纳米管。这些长的膜连接结构，称为隧道纳米管（TNTs），形成了细胞间的管道，并已被证明能够实现各种细胞成分和信号的运输。然而，TNT形成的分子基础仍有待阐明。在这里，我们报告一种哺乳动物蛋白M-Sec可诱导从质膜延伸出许多膜突起的从头形成，其中一些与相邻细胞相连并随后形成类似TNT的结构。通过RNA干扰（RNAi）使M-Sec缺失，可大大减少巨噬细胞系中内源性TNT的形成以及钙通量的细胞间传播。此外，M-Sec与Ral及作为Ral下游效应器的外泌体复合物之间相互作用的阻断，减弱了膜纳米管的形成。我们的结果表明，M-Sec通过与Ral-外泌体途径相互作用，作为膜纳米管形成的关键调节因子发挥作用。
