Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
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DOI：
10.1016/j.devcel.2015.09.018
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发表时间：
2015-10-26
影响因子：
11.8
通讯作者：
Laporte, Jocelyn
中科院分区：
文献类型：
--
作者：
D'Alessandro, Manuela;Hnia, Karim;Laporte, Jocelyn
细胞核定位是细胞内组织、细胞分化和器官发育的关键，并在许多疾病中受到影响，包括由amphiphysin-2 （BIN1）改变引起的肌病。肌动蛋白和微管细胞骨架对细胞核定位至关重要，但它们在这一过程中的串扰很少被表征。在这里，我们报道了秀丽隐杆线虫、哺乳动物细胞或来自核中心性肌病患者的肌肉中amphiphysin/BIN1的损伤会改变核的位置和形状。我们发现AMPH-1/BIN1在这两个物种中都与nesprin和actin以及微管结合蛋白CLIP170结合。CLIP170的微管锚定CAP-GLY结构域与nesprin的核包膜锚定KASH结构域融合表达，可挽救amph-1突变体的核定位缺陷。因此，Amphiphysins在连接核膜与肌动蛋白和微管细胞骨架方面起着核心作用。我们认为BIN1在肌病中改变的核定位中具有直接和进化保守的作用。
Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.