Role of the Fragilis Proteins in the Immune Response

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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.