The Molecular Basis of Allorecognition in Social Amoeba

描述(申请人提供)：自我/非我的认可是生活的一个基本方面。导致组织、器官和多细胞生物体的细胞合作的进化被认为需要发展出强大的自我/非我识别或异体识别机制，以防止来自遗传上不同的竞争对手的剥削。社会阿米巴是一种优秀的模型系统，对发育过程中的细胞黏附、信号传递和组织形成进行了广泛的研究，并为其开发了强大的分子遗传学工具。我们认为，在盘状芽孢杆菌的发育过程中，细胞整合了黏附和交流，通过有利于基因相关个体之间共同产孢子的同种识别过程，优化了细胞合作。盘状芽孢杆菌的野生分离株表现出与它们的遗传亲缘关系直接成比例的合作行为，我们已经发现了一个蛋白质家族，它可能构成这种合作的分子基础的一部分。这个想法是基于我们的发现，即黏附蛋白LagC1和相关蛋白LagB1是将细胞整合到多细胞组织所需的细胞合作所必需的，它们的基因是共同调节的，两者都显示出正向或平衡选择的证据，暗示着适应性进化，并且它们的序列多态与同种异体识别很好地相关。LagC1型基因在人类基因组中也是丰富和多态的，这表明我们在Dictyostelius中发现的机制可能与人类发育和天然免疫有关并适用。我们假设，在一般情况下，高度多态的膜蛋白可能介导同种异体识别，而特定的蛋白质LagB1和LagC1通过等位基因特异性的细胞间黏附和信号相互作用，介导同种异体识别，从而有利于遗传相似个体的合作产孢子形成。为了验证这些假说，我们将搜索网柄菌基因组中编码多态跨膜蛋白的基因，并测试它们与野生菌株之间同种异体识别(分离)的相关性。我们将在研究LagB1和LagC1在这一过程中的具体作用之后，通过突变和基因替换的方法进一步研究最相关的蛋白质在同种异体识别中的作用。公共卫生相关性：人类的同种异体识别(自我/非我识别)主要是通过我们的适应性免疫系统实现的，其高效掩盖了其他机制的潜在活动，例如在许多物种之间保守的先天免疫系统。然而，在一些患者群体中，由于艾滋病或癌症、移植或自身免疫性疾病的免疫抑制治疗，适应性免疫系统正在失效。我们正在研究的蛋白质家族在人类基因组中有很好的代表性，但人们对其在同种异体识别中的功能知之甚少，所以在一个简单的模型系统中进行研究，如盘基网柄菌，将使我们能够使用高分辨率的方法来了解它们的功能，这些方法要么无法在人类身上实现，要么很难实现。

DESCRIPTION (provided by applicant): Self/nonself recognition is a fundamental aspect of life. The evolution of cellular cooperation that led to tissues, organs and multicellular organisms is thought to have required the development of robust mechanisms of self/nonself recognition, or allorecognition, to preclude exploitation by genetically dissimilar competitors. The social amoeba, Dictyostelium discoideum, is an excellent model system in which cell adhesion, signaling and tissue formation during development have been studied extensively and for which powerful molecular genetic tools have been developed. We propose that cells integrate adhesion and communication during D. discoideum development to optimize cellular cooperation through a process of allorecognition that favors communal sporulation between genetically related individuals. Wild isolates of D. discoideum display cooperative behavior that is directly proportional to their genetic relatedness and we have uncovered a family of proteins that may form part of the molecular basis for this cooperation. This idea is based on our findings that the adhesion protein LagC1 and the related protein LagB1 are required for the cellular cooperation needed to integrate cells into a multicellular tissue, their genes are co-regulated, both display evidence of positive or balancing selection, suggestive of adaptive evolution, and their sequence polymorphism correlates well with allorecognition. Genes of the LagC1 type are abundant and polymorphic in the human genome as well, suggesting that the mechanisms we find in Dictyostelium would be relevant and applicable to human development and innate immunity. We hypothesize that highly polymorphic membrane proteins may mediate allorecognition in general, and that the specific proteins LagB1 and LagC1 interact functionally to mediate allorecognition through allele-specific intercellular adhesion and signaling, thus favoring cooperative sporulation of genetically similar individuals. To test these hypotheses, we will search the Dictyostelium genome for genes that encode polymorphic transmembrane proteins and test their correlation with allorecognition (segregation) between wild strains. We will further study the role of the most correlated proteins in allorecognition using mutagenesis and gene replacement approaches following the example of studying the specific roles of LagB1 and LagC1 in the process. PUBLIC HEALTH RELEVANCE: Allorecognition (self/nonself recognition) in humans is mainly achieved by our adaptive immune system whose high efficiency obscures the potential activity of other mechanisms, such as innate immunity systems that are conserved between numerous species. Nevertheless, there are groups of patients in which the adaptive immune system is failing due to AIDS or immune suppressive treatments in cases of cancer, transplantation or autoimmune diseases. The protein family we are studying is well represented in the human genome but little is known about its function in allorecognition, so studies in a simple model system such as Dictyostelium discoideum would allow us to understand their function using high-resolution methods that are either unavailable or hard to implement in humans.