Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
EMBO J. 2013 Jul 17;32(14):2056-72. doi: 10.1038/emboj.2013.131. Epub 2013 Jun 4.
The vesicle-associated membrane protein (VAMP) associated protein B (VAPB) is an integral membrane protein localized to the endoplasmic reticulum (ER). The P56S mutation in VAPB has been linked to motor neuron degeneration in amyotrophic lateral sclerosis type 8 (ALS8) and forms ER-like inclusions in various model systems. However, the role of wild-type and mutant VAPB in neurons is poorly understood. Here, we identified Yip1-interacting factor homologue A (YIF1A) as a new VAPB binding partner and important component in the early secretory pathway. YIF1A interacts with VAPB via its transmembrane regions, recycles between the ER and Golgi and is mainly localized to the ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons. VAPB strongly affects the distribution of YIF1A and is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. When VAPB-P56S is present, YIF1A is recruited to the VAPB-P56S clusters and loses its ERGIC localization. These data suggest that both VAPB and YIF1A are important for ER-to-Golgi transport and that missorting of YIF1A may contribute to VAPB-associated motor neuron disease.
囊泡相关膜蛋白 (VAMP) 相关蛋白 B (VAPB) 是一种定位于内质网 (ER) 的完整膜蛋白。VAPB 中的 P56S 突变与肌萎缩侧索硬化症 8 型 (ALS8) 中的运动神经元变性有关，并在各种模型系统中形成 ER 样包含物。然而，野生型和突变型 VAPB 在神经元中的作用知之甚少。在这里，我们鉴定了 Yip1 相互作用因子同源物 A (YIF1A) 为 VAPB 的新结合伴侣，也是早期分泌途径中的重要组成部分。YIF1A 通过其跨膜区域与 VAPB 相互作用，在 ER 和高尔基体之间循环，并主要定位于大鼠海马神经元的 ER-Golgi 中间隔室 (ERGICs)。VAPB 强烈影响 YIF1A 的分布，并且是将细胞内膜运输到树突和正常树突形态所必需的。当存在 VAPB-P56S 时，YIF1A 被募集到 VAPB-P56S 簇中并失去其 ERGIC 定位。这些数据表明，VAPB 和 YIF1A 对于 ER 到高尔基体的运输都很重要，并且 YIF1A 的错误分拣可能导致与 VAPB 相关的运动神经元疾病。
