Regulation of membrane trafficking by Coronins

摘要 Coronins家族在调节肌动蛋白中起着重要的作用 驱动细胞迁移、极性、细胞形状和细胞内运输的网络，以及 从而有助于从先天免疫到 神经信号然而，这些职能和活动的特点是， 典型的科罗尼。与此形成鲜明对比的是，我们对细胞的 作用和肌动蛋白细胞骨架调节的结构不同类的串联 冠蛋白，其包括冠蛋白7（Coro 7）、POD-1和CorB。我们的初步数据 表明哺乳动物Coro 7可以控制Arp 2/3介导的成核，尽管 这一活动背后的机制仍然难以捉摸。此外，我们表明，这种肌动蛋白- 调节活性可以调节NPF诱导的肌动蛋白网络， 膜运输，包括自噬，细胞使用的过程，以处置 有害的细胞器、错误折叠的蛋白质和有毒的聚集体。采用多学科 包括最先进的生物化学、生物物理学、遗传学和实时成像的方法 我们在这里提出的技术来阐明1）Coro 7如何在结构上与Arp 2/3相互作用， 2)Coro 7如何通过成核机制抑制Arp 2/3介导的成核 促进因子，3）其他Arp 2/3调节因子，以及4）这些肌动蛋白调节因子 Coro 7的活动调节分支肌动蛋白网络的周转， 自噬

ABSTRACT The extensive family of the Coronins plays an important role in regulating the actin networks that drive cell migration, polarity, cell shape and intracellular trafficking, and thereby contribute to essential biological processes ranging from innate immunity to neuronal signaling. However, these functions and activities have been characterized for the canonical Coronins. In stark contrast, we know next to nothing about the cellular roles and actin cytoskeleton regulation of the structurally distinct class of the tandem Coronins, which comprises Coronin 7 (Coro7), POD-1, and CorB. Our preliminary data show that mammalian Coro7 can control Arp2/3-mediated nucleation, although the mechanism underlying this activity remains elusive. In addition, we show that this actin- regulatory activity can regulate NPF-induced actin networks that drive intracellular membrane transport, including autophagy, a process used by cells to dispose of unwanted organelles, misfolded proteins and toxic aggregates. Using a multidisciplinary approach comprising state-of-the-art biochemical, biophysical, genetic and live-imaging techniques we propose here to elucidate 1) how Coro7 structurally interacts with Arp2/3, 2) how Coro7 mechanistically inhibits Arp2/3-mediated nucleation by nucleation promoting factors, and 3) by other Arp2/3 regulators, and 4) how these actin-regulatory activities of Coro7 regulate the turnover of the branched actin networks that drive autophagy.