Role of the Fragilis Proteins in the Immune Response

描述（由申请人提供）：fragilis基因家族代表了一组相对未知的干扰素β诱导基因/基因产物，其与免疫应答的下调有关。人类和小鼠基因组分别拥有3至5个该家族成员的拷贝。最熟知的是人蛋白Leu-13，其被描述为T细胞、B细胞和单核细胞上的许多信号转导复合物的成分。这些复合物中最著名的是人B细胞上的补体受体CR2复合物。事实上，还没有关于这种蛋白质如何影响这种信号传导的研究，尽管很明显它确实起着下调作用。我们建议利用R21应用程序的独特格式来测试一个新的假设：脆弱蛋白是泛素修饰途径的成员。具体来说，我们建议fragilis蛋白的功能在膜内标记关键的调控蛋白，无论是细胞表面蛋白或膜相关的信号转导蛋白，与泛素（或泛素家族成员）。然后，该标签可以用于改变这些信号分子的活性或通过蛋白体途径靶向它们进行破坏。我们将耦合这一假设定义的类型的膜调控复合物的fragilis蛋白的一部分，并表征工程敲除动物的表型，缺乏一个鼠fragilis基因，fragilis 5，这是优先在巨噬细胞中表达。通过结合从这些方法获得的数据，我们希望已经描述了一组特定的功能，脆弱的蛋白质，以及定义的细胞类型和特定的信号转导途径，他们修改。这些蛋白质代表在抗原特异性应答（B细胞受体、T细胞受体等）内起作用的分子与先天性免疫应答的分子之间的又一桥梁。

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.