Role of the Fragilis Proteins in the Immune Response

描述(申请人提供)：Fragilis基因家族代表一组相对未知的β干扰素诱导基因/基因产物，这些基因/基因产物与免疫反应的下调有关。人类和小鼠的基因组分别拥有这个家族成员的3到5个拷贝。最广为人知的是人类蛋白Leu-13，它被描述为T细胞、B细胞和单核细胞上的许多信号转导复合体的组成部分。其中最著名的是人类B细胞上的补体受体CR2复合体。几乎还没有关于这种蛋白质如何影响这种信号的研究，尽管很明显它确实起到了向下调节的作用。我们建议利用R21应用的独特形式来检验一个新的假设：脆性蛋白是泛素修饰途径的成员。具体地说，我们认为脆性蛋白在膜内发挥作用，以泛素(或泛素家族成员)标记关键调控蛋白，无论是细胞表面蛋白还是膜相关信号转导蛋白。然后，这个标签可以改变这些信号分子的活性，或者通过蛋白小体途径靶向破坏它们。我们将把这一假设与定义脆性蛋白所属的膜调节复合体的类型结合起来，并描述缺乏小鼠脆性基因之一的工程化敲除动物的表型，脆性基因5是在巨噬细胞中优先表达的。通过结合这些方法获得的数据，我们希望已经描述了脆性蛋白的一组特定的功能，并定义了它们修改的细胞类型和特定的信号转导途径。这些蛋白质代表了在抗原特异性反应中起作用的分子(B细胞受体、T细胞受体等)和先天免疫反应分子之间的另一座桥梁。

DESCRIPTION (provided by applicant): The fragilis gene family represents a relatively unknown group of interferon beta inducible genes/gene products who have been implicated in the down modulation of the immune response. The human and mouse genomes possess 3 to 5 copies of members of this family, respectively. The most well known is the human protein Leu-13 that has been described as a constituent of a number of signal transduction complexes on T cells, B cells and monocytes. The best known of these complexes is the complement receptor CR2 complex on human B cells. Virtually no studies have been carried out on how this protein can influence such signaling although it is clear it does play a down modulatory role. We propose to utilize the unique format of the R21 application to test a novel hypothesis: that the fragilis proteins are members of a ubiquitin modification pathway. Specifically we propose that the fragilis proteins function within the membrane to tag key regulatory proteins, either cell surface proteins or membrane associated signal transduction proteins, with ubiquitin (or ubiquitin family members). This tag can then act to either modify the activity of these signaling molecules or target them for destruction via the proteosome pathway. We will couple this hypothesis with defining the types of membrane regulatory complexes that the fragilis proteins are part of, and to characterize the phenotype of an engineered knockout animal that is lacking one of the murine fragilis genes, fragilis5, that is preferentially expressed in macrophages. By combining the data obtained from these approaches we hope to have described a specific set of functions for the fragilis proteins as well as to have defined the cell types and specific signal transduction pathways that they modify. These proteins represent yet another bridge between the molecules that function within the antigen specific response (B cell receptor, T cell receptor, etc) and those of the innate immune response.