The molecular basis of allorecognition and its roles in development and evolution of the social amoeba D. discoideum

同种异体识别的分子基础及其在社会性盘状变形虫发育和进化中的作用

• 批准号: 9067758
• 负责人: GAD SHAULSKY
• 金额: $ 50.28万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-12 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067758
• 关键词: Affinity; Amino Acid Sequence; Amoeba genus; Animal Model; Binding; Biological Models; Cell Polarity; Cell physiology; Cells; Cellularity; Chemicals; Chemotaxis; Cues; Cyclic AMP; Development; Dictyostelium; Dictyostelium discoideum; Embryonic Development; Essential Genes; Event; Evolution; Food; Gene Expression; Genetic Polymorphism; Genome; Graft Rejection; Health; Immune system; Individual; Infection; Inflammation; Life; Link; Longitudinal Studies; Major Histocompatibility Complex; Mammals; Mediating; Medicine; Membrane Proteins; Molecular; Molecular Genetics; Natural Immunity; Organism; Parasites; Pathway interactions; Population; Process; Property; Proteins; Role; Signal Transduction; Societies; Soil; Specificity; Surface; System; Tissues; base; cell behavior; cost; extracellular; interest; marine organism; public health relevance; segregation; social; tool

 DESCRIPTION (provided by applicant): Allorecognition is defined as the ability of organisms to distinguish self from non-self, a common theme in many organisms and a central component in the evolution of multicellularity and cooperation. In mammals, allorecognition is mediated by the Major Histocompatibility Complex (MHC), which is part of the immune system. The MHC facilitates identification of parasites in infection processes and graft rejection in transplantatin medicine. There is evidence for the involvement of other proteins in graft rejection but there are very few model systems available to study these proteins. There are numerous allorecognition systems in non- mammalian systems, notably in marine organisms, but most of them are not amenable to manipulation with molecular genetic tools. We have found an allorecognition system in the social soil amoeba Dictyostelium discoideum, opening the field to molecular genetic exploration of concepts in allorecognition and cooperation at various levels - from molecules and cells to tissues, genomes and societies. The Dictyostelium allorecognition system is based on two proteins, TgrB1 and TgrC1, that share many properties with mammalian MHC proteins, but not their amino acid sequences. These trans-membrane proteins are highly polymorphic in natural Dictyostelium populations and they are necessary and sufficient for allorecognition. Dictyostelium cells live as free amoebae in the soil when food is abundant but they aggregate into multicellular organisms when starved. Aggregation involves chemotaxis to extracellular cAMP and Dictyostelium is one of the best model systems for the study of chemotaxis, which is a central process in embryogenesis and in innate immunity. When Dictyostelium cells encounter cells that carry incompatible TgrB1 and TgrC1 during aggregation, they segregate from one another and form separate multicellular organisms. This segregation protects cells from cheaters, which are individuals that take advantage of social benefits without paying the full cost of cooperation. We propose that TgrB1 on the surface of one cell binds TgrC1 on the surface of an adjacent cell and that binding initiates a signal transduction cascade that alters cell behavior. We plan to investigate this system at four levels. At the protein level, we will explore the properties that define TgrB1-TgrC1 binding affinity and specificity and the mechanisms that mediate downstream signal transduction. At the cell level, we will study the pathways that transduce the allorecognition signals immediately after TgrB1 binds TgrC1, leading to changes in chemotaxis and cell polarity. At the developmental level, we will study the long-term events that change gene expression and cell physiology after cells segregate from incompatible cells and cooperate with compatible cells to form tissues. At the genome level, we are interested in how the two developmentally essential genes co-evolve and maintain polymorphism in the population.

 描述（由申请人提供）：异体识别被定义为生物体区分自我与非自我的能力，这是许多生物体的共同主题，也是多细胞和合作进化的核心组成部分。在哺乳动物中，同种异体识别是由主要组织相容性复合体 (MHC) 介导的，它是免疫系统的一部分。 MHC 有助于识别感染过程中的寄生虫和移植医学中的移植物排斥反应。有证据表明其他蛋白质参与移植物排斥反应，但可用于研究这些蛋白质的模型系统很少。非哺乳动物系统中有许多同种异体识别系统，特别是在海洋生物中，但其中大多数不适合用分子遗传工具进行操作。我们在社会土壤阿米巴盘基网柄菌中发现了同种异体识别系统，为从分子和细胞到组织、基因组和社会等各个层面的同种异体识别和合作概念的分子遗传学探索开辟了领域。盘基网柄菌同种识别系统基于 TgrB1 和 TgrC1 两种蛋白质，它们与哺乳动物 MHC 蛋白质具有许多相同的特性，但氨基酸序列不同。这些跨膜蛋白在天然盘基网柄菌种群中具有高度多态性，并且它们对于同种异体识别是必要且充分的。当食物充足时，盘基网柄菌细胞作为游离变形虫生活在土壤中，但当饥饿时，它们会聚集成多细胞生物。聚集涉及细胞外 cAMP 的趋化性，盘基网柄菌是研究趋化性的最佳模型系统之一，趋化性是胚胎发生和先天免疫的核心过程。当盘基网柄菌细胞在聚集过程中遇到携带不相容的 TgrB1 和 TgrC1 的细胞时，它们会彼此分离并形成单独的多细胞生物体。这种隔离可以保护细胞免受作弊者的侵害，这些作弊者利用社会福利而不支付全部合作成本。我们提出，一个细胞表面的 TgrB1 与相邻细胞表面的 TgrC1 结合，这种结合会启动信号转导级联，从而改变细胞行为。我们计划在四个层面上调查这个系统。在蛋白质水平上， 我们将探索定义 TgrB1-TgrC1 结合亲和力和特异性的特性以及介导下游信号转导的机制。在细胞水平上，我们将研究 TgrB1 与 TgrC1 结合后立即转导同种异体识别信号的途径，从而导致趋化性和细胞极性的变化。在发育水平上，我们将研究细胞与不相容细胞分离并与相容细胞合作形成组织后改变基因表达和细胞生理学的长期事件。在基因组水平上，我们感兴趣的是这两个发育必需基因如何在群体中共同进化并维持多态性。