The polymeric immunoglobulin receptor (plgR) is made by many mucosal epithelial cells ands transports the polymeric immunoglobulins, dimeric IgA (dlgA) and in some cases IgM, into external secretions, where the dlgA form the first adaptive immunologic defense against infection. Newly made plgR is first delivered to the basolateral surface of the epithelial cell, where it can bind dlgA. The plgR is then endocytosed and, via a series of endosomal compartments, is transcytosed to the apical surface. There the plgR is proteolytically cleaved and the extracellular, ligand binding domain is released together with the dlgA. This cleaved fragment is called secretory component and serves to protect the dlgA against degradation. Although the plgR is constitutively transcytosed in the absence of dlgA, binding of dlgA increases the rate of transcytosis. This allows the plgR to transport increased levels of dlgA, which may be produced during mucosal infection or inflammation. Binding of dlgA to plgR initiates a complex signaling cascade. One of the earliest steps is the activation of p62Yes, a Src-family non-receptor tyrosine kinase, which interacts indirectly with the plgR. We have identified the epidermal growth factor receptor (EGFR) as a major direct substrate of p62Yes, and EGFR is phosphorylated by p62Yes in response to dlgA binding. Here we will analyze how EGFR and p62Yes work together to control dlgA-stimulated transcytosis. Rab3b is a member of the Rab family of small GTPases that regulate membrane traffic. We have found that Rab3b binds directly to the cytoplasmic domain of plgR. Binding of dlgA to plgR causes Rab3b to hydrolyze its bound GTP and to dissociate from the plgR, thereby increasing plgR transcytosis. We will analyze how Rab3b controls plgR transcytosis. IgA nephropathy is the most common form of nephritis world-wide and a major cause of end stage renal disease. Nasopharyngeal carcinoma is caused by infection with Epstein-Barr virus. Entry of the virus can be promoted by binding of virus-specific dlgA, which binds to the plgR on nasopharyngeal cells. Both IgA nephropathy and nasopharyngeal carcinoma are associated with a single nucleotide polymorphism, which causes a point mutation in the plgR. We will analyze the effects of this point mutation on plgR trafficking and function in vitro system, using mutant plgR expressed in Madin-Darby canine kidney epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036953-14
Application #
7434312
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Rothermel, Annette L
Project Start
1995-09-30
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
14
Fiscal Year
2008
Total Cost
$281,840
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Verges, Marcel; Sebastian, Isabel; Mostov, Keith E (2007) Phosphoinositide 3-kinase regulates the role of retromer in transcytosis of the polymeric immunoglobulin receptor. Exp Cell Res 313:707-18
Verges, Marcel; Bensadoun, Andre; Herz, Joachim et al. (2004) Endocytosis of hepatic lipase and lipoprotein lipase into rat liver hepatocytes in vivo is mediated by the low density lipoprotein receptor-related protein. J Biol Chem 279:9030-6
Zegers, Mirjam M P; O'Brien, Lucy E; Yu, Wei et al. (2003) Epithelial polarity and tubulogenesis in vitro. Trends Cell Biol 13:169-76
Luton, F; Verges, M; Vaerman, J P et al. (1999) The SRC family protein tyrosine kinase p62yes controls polymeric IgA transcytosis in vivo. Mol Cell 4:627-32
Luton, F; Mostov, K E (1999) Transduction of basolateral-to-apical signals across epithelial cells: ligand-stimulated transcytosis of the polymeric immunoglobulin receptor requires two signals. Mol Biol Cell 10:1409-27
Verges, M; Havel, R J; Mostov, K E (1999) A tubular endosomal fraction from rat liver: biochemical evidence of receptor sorting by default. Proc Natl Acad Sci U S A 96:10146-51
Singer, K L; Mostov, K E (1998) Dimerization of the polymeric immunoglobulin receptor controls its transcytotic trafficking. Mol Biol Cell 9:901-15
Leung, S M; Chen, D; DasGupta, B R et al. (1998) SNAP-23 requirement for transferrin recycling in Streptolysin-O-permeabilized Madin-Darby canine kidney cells. J Biol Chem 273:17732-41
Luton, F; Cardone, M H; Zhang, M et al. (1998) Role of tyrosine phosphorylation in ligand-induced regulation of transcytosis of the polymeric Ig receptor. Mol Biol Cell 9:1787-802
Low, S H; Roche, P A; Anderson, H A et al. (1998) Targeting of SNAP-23 and SNAP-25 in polarized epithelial cells. J Biol Chem 273:3422-30

Showing the most recent 10 out of 18 publications