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.
|Cho, Jin A; Zhang, Xuan; Miller, Gregory M et al. (2014) 4-Phenylbutyrate attenuates the ER stress response and cyclic AMP accumulation in DYT1 dystonia cell models. PLoS One 9:e110086|
|te Welscher, Yvonne M; Chinnapen, Daniel J-F; Kaoutzani, Lydia et al. (2014) Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1. J Control Release 175:72-8|
|Zhou, Xiaohui; Massol, Ramiro H; Nakamura, Fumihiko et al. (2014) Remodeling of the intestinal brush border underlies adhesion and virulence of an enteric pathogen. MBio 5:|
|Cho, Jin A; Lee, Ann-Hwee; Platzer, Barbara et al. (2013) The unfolded protein response element IRE1* senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13:558-69|
|Weflen, Andrew W; Baier, Nina; Tang, Qing-Juan et al. (2013) Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules. Mol Biol Cell 24:2398-405|
|Rath, Timo; Kuo, Timothy T; Baker, Kristi et al. (2013) The immunologic functions of the neonatal Fc receptor for IgG. J Clin Immunol 33 Suppl 1:S9-17|
|Baker, Kristi; Rath, Timo; Lencer, Wayne I et al. (2013) Cross-presentation of IgG-containing immune complexes. Cell Mol Life Sci 70:1319-34|
|Saslowsky, David E; te Welscher, Yvonne M; Chinnapen, Daniel J-F et al. (2013) Ganglioside GM1-mediated transcytosis of cholera toxin bypasses the retrograde pathway and depends on the structure of the ceramide domain. J Biol Chem 288:25804-9|
|Fortin, Jean-Philippe; Chinnapen, Daniel; Beinborn, Martin et al. (2011) Discovery of dual-action membrane-anchored modulators of incretin receptors. PLoS One 6:e24693|
|Saslowsky, David E; Cho, Jin Ah; Chinnapen, Himani et al. (2010) Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2. J Clin Invest 120:4399-4409|