Understanding fish immune receptor-mediated control of the phagocytic process

吞噬作用是一种先天细胞免疫防御反应，涉及识别、吞噬和最终破坏细胞外目标，如细菌。吞噬是所有动物的重要免疫机制，已从单细胞生物的原始营养获取过程演变为所有复杂的多细胞动物的基本先天防御和体内平衡过程。执行吞噬作用的细胞被称为吞噬细胞，这些特化细胞的活性取决于它们表达特定的细胞表面蛋白。这些蛋白结合靶标，然后触发信号级联，激活肌动蛋白依赖的膜重塑事件，这是主动捕获和吞噬靶标所必需的。每个吞噬受体作为细胞表面蛋白存在，包含细胞外区域，为目标识别提供界面，以及细胞内细胞质尾部，负责触发与肌动蛋白细胞骨架偶联的亚细胞信号事件。尽管了解哺乳动物的吞噬机制，但对其他动物的这种重要免疫反应知之甚少。缺乏这种原始防御策略的信息是一个明显的空白，可以使用基础脊椎动物免疫模型（如鱼）来填补。最近，我们的工作表明，某些鱼类免疫蛋白可以通过与典型哺乳动物途径保守的机制来控制吞噬。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作用。我们还证明了这种独特的吞噬途径在鱼类中与质膜衍生的突起的产生有独特的关联，这些突起积极参与细胞外靶标的捕获。跟踪活细胞中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，一种特定的硬骨鱼受体介导的途径可以选择性地控制质膜突起的形成。这种依赖于肌动蛋白的膜延伸，通常被称为丝状足或细胞触手，与许多生物过程的调节有关，包括细胞粘附、细胞迁移以及肿瘤侵袭。也就是说，我们对丝状足形成时空动态的受体和分子机制的了解非常有限。我们提出的研究将为吞噬过程中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塑事件，包括丝状足的产生。

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.