Greater than 90 percent of all infectious agents enter the body through exposed mucosal surfaces. Polymeric IgA and IgM are taken up by a variety of epithelial cells and transported across the cell into secretions such as milk, bile, saliva and secretions in the lung, intestine, and genitourinary tract where they form the first immunological defense against these infections. Recent studies showed that binding of dIgA to the pIgR stimulates the rate of pIgR transcytosis across the epithelium. The physiological function of this stimulation is that as production of dIgA is increased during infection the transcytosis of the IgA by the pIgR is correspondingly increased ensuring that sufficient quantities of specific dIgA are delivered to the site of infection. By this mechanism the transcytosis of IgA is coordinated with other aspects of the mucosal immune response. The goal of this grant is to understand the signaling mechanism by which IgA binding to the pIgR stimulates transcytosis. We have found that IgA binding to the pIgR activates a Src-family non-receptor protein tyrosine kinase, p62YES. Mice that have their p62Yes knocked-out transcytose less IgA and are much less able to transcytose an increased load of IgA. The p62Yes co‑immunoprecipitates with the pIgR indicating a physical association, though this association is probably indirect. Our focus is on how p62Yes interacts with pIgR and how p62Yes stimulates transcytosis. We will test the following hypotheses: 1). The pIgR and p62Yes interact in glycolipid-cholesterol rafts. 2). The pIgR and p62Yes interact in specific parts of the cells such as the basolateral plasma membrane and/or specific endosomal compartments. 3). Other proteins are involved in the coupling of pIgR and p62Yes. We have already identified one candidate, an alternatively spliced form of protein 4.1. Other candidate proteins probably exist as suggested by 2-hybrid and co-immunoprecipitation data. 4). Preliminary data indicate that there are specific substrates for p62Yes and we will identify these and test their roles in stimulation of transcytosis.
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