Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors
Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors
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DOI：
10.1016/j.devcel.2011.12.009
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发表时间：
2012-02-14
影响因子：
11.8
通讯作者：
Miller, Michael A.
中科院分区：
文献类型：
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作者：
Han, Sung Min;Tsuda, Hiroshi;Miller, Michael A.
VAPB/ALS8主要精子蛋白结构域（vMSP）与肌萎缩性侧索硬化症和脊髓性肌萎缩有关，但其在神经系统中的功能尚不清楚。在秀丽隐杆线虫和果蝇中，vMSP从其跨膜锚点上断裂，并以细胞类型特异性的方式分泌。我们发现神经元分泌的vmsp作用于横纹肌中表达的lar样蛋白酪氨酸磷酸酶和Roundabout生长锥引导受体。该信号通路促进arp2 /3依赖性肌动蛋白重塑和线粒体定位到富含肌动蛋白的肌i带。秀丽隐杆线虫VAPB突变体具有线粒体定位、形态、流动性和裂变/融合缺陷，这些缺陷被lar样受体或Arp2/3失活抑制。因此，重塑肌动蛋白细胞骨架的生长锥引导受体通路对线粒体产生了意想不到的影响！动力学。我们认为神经元分泌vmsp促进横纹肌能量的产生和代谢，部分通过调节线粒体定位和功能。
The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondria! dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.