Institute of Cell Biology, Department of Biology, ETH Zürich, Zürich, Switzerland.
Brain. 2010 Aug;133(Pt 8):2462-74. doi: 10.1093/brain/awq168.
Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.
Charcot-Marie-Tooth 神经病患者和基因靶向小鼠揭示了 SH3TC2 基因在外周神经髓鞘形成中的重要作用。SH3TC2 在周围神经系统中的施万细胞中表达受限，并且该基因产物 SH3TC2 定位于核周再循环隔室。在这里，我们表明 SH3TC2 与小 GTP 酶 Rab11 相互作用，已知 Rab11 调节内化膜和受体回收到细胞表面的再循环。蛋白结合研究和转铁蛋白受体运输的结果与 SH3TC2 作为 Rab11 效应分子的作用一致。与 Rab11 在施万细胞髓鞘形成中的功能一致，导致神经病的 SH3TC2 突变破坏了 SH3TC2/Rab11 相互作用，并且强制表达显性负性 Rab11 强烈损害体外髓鞘形成。我们的数据表明，SH3TC2/Rab11 相互作用与周围神经病理生理学有关，并将内体再循环纳入参与施万细胞髓鞘形成的细胞机制列表中。
