The Molecular Basis of Allorecognition in Social Amoeba

自我/非自我识别是生活的一个基本方面。细胞合作的进化导致了组织、器官和多细胞生物的出现，这被认为需要发展出强大的自我/非自我识别机制，或同种异体识别机制，以防止基因上不同的竞争对手利用。社会阿米巴，Dictyosteelium discoideum，是一个很好的模型系统，其中细胞粘附，信号和组织形成在发展过程中已被广泛研究，并已开发出强大的分子遗传工具。我们认为细胞在D.盘状突发育，通过有利于遗传相关个体之间的公共孢子形成的同种识别过程来优化细胞合作。D. discoideum显示出与它们的遗传相关性成正比的合作行为，我们已经发现了一个蛋白质家族，可能构成这种合作的分子基础。这个想法是基于我们的研究结果，即粘附蛋白LagC 1和相关蛋白LagB 1是将细胞整合到多细胞组织中所需的细胞合作所必需的，它们的基因是共同调节的，两者都显示出阳性或平衡选择的证据，暗示了适应性进化，并且它们的序列多态性与同种异体识别密切相关。LagC 1型基因在人类基因组中也是丰富和多态的，这表明我们在网骨藻中发现的机制与人类发育和先天免疫相关并适用。我们假设，高度多态性的膜蛋白可能介导的allorecognition一般，和特定的蛋白质LagB 1和LagC 1相互作用功能介导allorecognition通过等位基因特异性细胞间粘附和信号，从而有利于合作孢子形成的遗传相似的个人。为了验证这些假设，我们将搜索网囊藻基因组中编码多态性跨膜蛋白的基因，并测试它们与野生株之间的同种识别（分离）的相关性。我们将进一步研究最相关的蛋白质在同种异体识别中的作用，使用诱变和基因置换的方法以下的例子，研究在该过程中的特定作用的LagB 1和LagC 1。公共卫生相关性：人类的同种异体识别（自我/非自我识别）主要是通过我们的适应性免疫系统实现的，其高效率掩盖了其他机制的潜在活性，例如在许多物种之间保守的先天免疫系统。然而，有一些患者群体的适应性免疫系统由于艾滋病或癌症、移植或自身免疫性疾病情况下的免疫抑制治疗而失败。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，但对它在同种识别中的功能知之甚少，因此在一个简单的模型系统中进行研究，如Dictyosteelium discoideum，将使我们能够使用高分辨率的方法来理解它们的功能，这些方法要么不可用，要么难以在人类中实现。

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.