Role of the Fragilis Proteins in the Immune Response

描述（由申请人提供）：脆弱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，它们与免疫反应的下调有关。人类和小鼠的基因组分别拥有3到5个该家族成员的拷贝。其中最著名的是人类蛋白Leu-13，它被描述为T细胞、B细胞和单核细胞上许多信号转导复合物的组成部分。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，尽管这种蛋白质确实发挥了下调调节作用，但还没有研究表明这种蛋白质是如何影响这种信号的。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：脆性蛋白是泛素修饰途径的成员。具体来说，我们提出脆性蛋白在膜内的功能是用泛素（或泛素家族成员）标记关键的调节蛋白，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，或者通过蛋白体途径靶向破坏它们。我们将结合这一假设，定义脆弱蛋白所在的膜调控复合物的类型，并表征一个缺乏小鼠脆弱基因之一的工程敲除动物的表型，脆弱基因5在巨噬细胞中优先表达。通过结合从这些方法中获得的数据，我们希望能够描述脆性蛋白的一组特定功能，并定义细胞类型和它们所修饰的特定信号转导途径。这些蛋白质代表了抗原特异性反应（B细胞受体、T细胞受体等）和先天免疫反应中起作用的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.