Understanding fish immune receptor-mediated control of the phagocytic process

吞噬作用是一种先天的细胞免疫防御反应，涉及识别、吞噬并最终破坏细胞外目标，如细菌。吞噬作用是所有动物免疫的重要机制，它已经从单细胞生物体原始的营养获取过程进化为所有复杂的多细胞动物的基本先天防御和动态平衡过程。执行吞噬功能的细胞被称为吞噬细胞，这些特化细胞的活动取决于它们对特定细胞表面蛋白的表达。这些蛋白质结合靶标，然后触发信号级联反应，激活主动捕获和吞噬靶标所需的肌动蛋白依赖的膜重构事件。每个吞噬细胞受体以细胞表面蛋白的形式存在，包含一个胞外区域，为靶标识别提供接口，以及一个胞内胞浆尾巴，负责触发耦合到肌动蛋白细胞骨架的亚细胞信号事件。尽管人们了解哺乳动物的吞噬机制，但对其他动物的这一重要免疫反应知之甚少。缺乏关于这种原始防御策略的信息是一个明显的空白，可以使用鱼类等基本脊椎动物免疫模型来填补这一空白。最近，我们的工作表明，某些鱼类免疫蛋白可以通过与原型哺乳动物途径保守的机制来控制吞噬作用。然而，其中一种鱼类免疫受体类型也被证明使用一种全新的机制激活吞噬功能。我们还证明，鱼类这种独特的吞噬途径与质膜衍生突起的产生独特相关，质膜衍生突起积极参与捕获细胞外目标。一个追踪活细胞中F-肌动蛋白动态的荧光报告显示，这些细胞突起的形成也需要肌动蛋白聚合的非典型模式。这些发现首次表明，特定的硬骨受体介导的途径可以选择性地控制质膜突起的形成。这种肌动蛋白依赖的膜延伸，通常被称为丝状足或细胞触角，参与了许多生物学过程的调节，包括细胞黏附、细胞迁移以及肿瘤侵袭性。也就是说，我们对受体和分子机制的了解非常有限，这些受体和分子机制有助于丝状足细胞形成的时空动态。我们提出的研究将对吞噬过程中的免疫调节受体信号事件提供具体的新细节，更广泛地说，有助于理解与其他基本细胞过程相关的动态膜重构事件，包括丝状伪足的产生。

Phagocytosis is an innate cellular immune defense response that involves the recognition, engulfment, and eventual destruction of extracellular targets such as bacteria. An important mechanism of immunity in all animals, phagocytosis has evolved from a primitive nutrient acquisition process by unicellular organisms into a fundamental innate defense and homeostatic processes in all complex multicellular animals. Cells that perform phagocytosis are called phagocytes and the activity of these specialized cells is dependent upon their expression of specific cell-surface proteins. These proteins bind targets and then trigger signaling cascades that activate actin-dependent membrane remodeling events required for the active capture and engulfment of targets. Each phagocytic receptor exists as a cell-surface protein containing an extracellular region, providing the interface for target recognition, as well as an intracellular cytoplasmic tail that is responsible for triggering the subcellular signaling events that couple to the actin cytoskeleton. Despite an understanding of phagocytic mechanisms in mammals, very little is known about this important immune response in other animals. The lack of information on such a primitive defense strategy is an obvious gap that can be filled using basal vertebrate immune models such as fish. Recently, our work has shown that certain fish immune proteins can control phagocytosis via mechanisms that are conserved with the prototypical mammalian pathways. However, one of these fish immune receptor-types was also shown to activate phagocytosis using a completely novel mechanism. We also demonstrated that this unique phagocytic pathway in fish was uniquely associated with the generation of plasma membrane-derived protrusions that actively participated in the capture of extracellular targets. A fluorescent reporter that tracks F-actin dynamics in live cells revealed that the formation of these cellular protrusions also required atypical patterns of actin polymerization. These findings suggest, for the first time, that a specific teleost receptor-mediated pathway can selectively control the formation of plasma membrane protrusions. Such actin-dependent membranous extensions, more commonly called filopodia or cellular tentacles, have been implicated in the regulation of numerous biological processes, including cell adhesion, cell migration, as well tumor invasiveness. That said, our knowledge of the receptors and molecular mechanisms that contribute to the spatiotemporal dynamics of filopodia formation are very limited. Our proposed studies will contribute specific new details into immunoregulatory receptor signaling events during phagocytosis and, more generally, towards understanding the dynamic membrane remodeling events that are associated with other fundamental cellular processes, including filopodia production.**