Understanding fish immune receptor-mediated control of the phagocytic process

了解鱼类免疫受体介导的吞噬过程控制

• 批准号: RGPIN-2017-05442
• 负责人: Stafford, James
• 金额: $ 2.91万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688146
• 关键词: Understanding; fish; immune; receptor; mediated

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.**

吞噬作用是一种先天的细胞免疫防御反应，涉及对细菌等细胞外靶标的识别，吞噬和最终破坏。吞噬作用是所有动物免疫的重要机制，它通过单细胞生物的原始营养获取过程演变为所有复杂多细胞动物的基本先天防御和稳态过程。进行吞噬作用的细胞称为吞噬细胞，这些专门细胞的活性取决于它们的特定细胞表面蛋白的表达。这些蛋白质结合了靶标，然后触发信号级联，以激活依赖肌动蛋白的膜重塑事件，需要进行主动捕获和吞噬靶标。每个吞噬受体都作为一个含有细胞外区域的细胞表面蛋白存在，为靶标识别提供了界面，以及负责触发伴有肌动蛋白细胞骨架的亚细胞信号事件的细胞内细胞质尾巴。尽管了解哺乳动物中的吞噬机制，但对其他动物的这种重要免疫反应知之甚少。缺乏关于这种原始防御策略的信息是一个明显的差距，可以使用基底脊椎动物免疫模型（例如鱼）来填补。最近，我们的工作表明，某些鱼类免疫蛋白可以通过原型哺乳动物途径保守的机制来控制吞噬作用。然而，这些鱼类免疫受体类型之一也显示出使用一种完全新颖的机制激活吞噬作用。我们还证明，这种独特的鱼类中的吞噬途径与积极参与细胞外靶标的质膜衍生突出的产生独特。一个跟踪活细胞中F-肌动力学的荧光记者表明，这些细胞突起的形成也需要非典型的肌动蛋白聚合模式。这些发现首次表明，特定的定量受体介导的途径可以选择性地控制质膜突起的形成。这种依赖性肌动蛋白依赖性膜扩展（通常称为丝状触角或细胞触角）与调节许多生物学过程有关，包括细胞粘附，细胞迁移以及肿瘤的侵入性。也就是说，我们对有助于丝状形成的时空动力学的受体和分子机制的了解非常有限。我们提出的研究将在吞噬作用期间为免疫调节受体信号传导事件提供特定的新细节，更普遍地是为了理解与其他基本细胞过程相关的动态膜重塑事件，包括丝状细胞的产生。** ** ** **