The overarching goal of this project is to elucidate how the IgG MHC Class I-like Fc3-receptor FcRn transports IgG and IgG-opsonized antigens into and across the intestinal barrier. Trafficking of IgG and associated IgG- complexes by FcRn in epithelial cells has important consequences on the dialogue between host and commensal microflora, and thus on epithelial maintenance, inflammatory responses and host defense at mucosal surfaces. We will test the hypotheses: 1) that intestinal epithelial cells utilize FcRn to neutralize IgG- opsonized microbes and microbial products and to raise an inflammatory response;2) that specific cellular factors associated with the common/apical recycling endosome, a compartment unique to polarized epithelial cells, regulate the trafficking of FcRn;and 3) that a membrane proximal amphipathic motif in the FcRn- cytoplasmic tail senses (or induces) membrane curvature or surface potential so as to affect receptor trafficking.
AIM 1 will characterize how IgG-opsonized particles divert FcRn from the transcytotic and recycling pathways, which typify FcRn trafficking, into the degradative pathway. We also will examine structure-function relationships of the FcRn cytoplasmic tail in this sorting step using FcRn-isoforms mutated in its cytoplasmic tail domain.
AIM 2 will follow-up on ideas raised in our recent studies indicating that the small GTPase Rab25 regulates a sorting step that specifies transcytosis.
We aim to identify and characterize the cellular factors of the common/apical recycling endosomes that regulate FcRn trafficking in polarized cells. Proteins to be studied include the FIP family of Rab11a/Rab25 effectors, Rab10, Rab8, ACAP1, and the exocyst complex. We will attempt an unbiased screen for FcRn-interacting proteins using a yeast two-hybrid system, and we will examine the apical and basolateral membrane SNAREs to see if these molecules mark FcRn-containing vesicles for vectorial transport across polarized cells.
AIM 3 will focus on the membrane proximal region of the FcRn cytoplasmic tail to test a new idea for sorting of membrane proteins by amphipathic 1-helical domains that sense (or induce) membrane curvature or surface potential. We propose that oligomerization of this motif explains how FcRn can internalize IgG-opsonized particles and switch pathways of trafficking away from recycling and transcytosis into degradative compartments.
We aim to understand one way that the intestine interacts with the vast and complex microflora and microbial products located in the intestinal lumen (cavity). Microbes in the intestinal lumen are strongly implicated in regulating intestinal function in health and disease, including the chronic inflammatory bowel diseases. Here, we study how an intestinal receptor for transporting immunoglobulin G (the most dominant form of antibodies in humans) dictates the outcome of this interaction.
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