Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Traffic. 2011 Nov;12(11):1620-33. doi: 10.1111/j.1600-0854.2011.01250.x. Epub 2011 Aug 5.
Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cellular defects that cause disease remain unclear, they are expected to be mild. To gain new insight into potential pathogenic mechanisms, we utilized mouse Dyn2 conditional knockout cells combined with retroviral-mediated reconstitution to mimic both heterozygous and homozygous states and characterized cellular phenotypes using quantitative assays for several membrane trafficking events. Surprisingly, none of the four mutants studied exhibited a defect in CME, but all were impaired in their ability to support p75/neurotrophin receptor export from the Golgi, the raft-dependent endocytosis of cholera toxin and the clathrin-independent endocytosis of epidermal growth factor receptor (EGFR). While it will be important to study these mutants in disease-relevant muscle and neuronal cells, given the importance of neurotrophic factors and lipid rafts in muscle physiology, we speculate that these common cellular defects might contribute to the tissue-specific diseases caused by a ubiquitously expressed protein.
动力蛋白（Dyn）是一种具有多个结构域和多功能的 GTP 酶，以其在网格蛋白介导的内吞作用（CME）中的重要作用而闻名。Dyn2 突变与两种人类疾病有关，中核肌病（CNM）和 Charcot-Marie-Tooth（CMT）疾病。矛盾的是，尽管 Dyn2 广泛表达且对胚胎发育至关重要，但与疾病相关的 Dyn2 突变体是常染色体显性遗传的，但会导致进展缓慢且组织特异性的疾病。因此，尽管导致疾病的细胞缺陷仍不清楚，但预计它们是轻微的。为了深入了解潜在的致病机制，我们利用小鼠 Dyn2 条件性敲除细胞结合逆转录病毒介导的重建来模拟杂合子和纯合子状态，并使用几种膜运输事件的定量测定来表征细胞表型。令人惊讶的是，在所研究的四个突变体中，没有一个在 CME 中表现出缺陷，但所有突变体都不能支持 p75/神经营养因子受体从高尔基体的输出、依赖筏的霍乱毒素内吞作用和表皮生长因子受体（EGFR）的网格蛋白独立内吞作用。虽然在与疾病相关的肌肉和神经元细胞中研究这些突变体非常重要，但鉴于神经营养因子和脂质筏在肌肉生理学中的重要性，我们推测这些常见的细胞缺陷可能导致由广泛表达的蛋白质引起的组织特异性疾病。
