RTG-ReMPro
Projects
P1 Becker-Pauly
Regulated ectodomain shedding of the polymeric immunoglobulin receptor (pIgR) in a multiprotein membrane tethered complex
Objectives
Our aim is to unravel the molecular properties of the membrane protein complex responsible for regulated and irreversible pIgR shedding. We will elucidate the constitutive shedding of meprin α/β by ADAM10/17 or MT1-MMP in complex with regulatory TSPAN8/15 and its impact on the cleavage of pIgR. Since meprin β, ADAM10, MT1-MMP, and interacting TSPANs can be modified by palmitoylation (unpublished data for meprin β and ADAM10, (60, 61), respectively), we will investigate if the reversible lipidation directly contributes to the regulation of the shedding complex. Antibacterial defense through mucosal IgA release via transcytosis of the pIgR might explain why decreased expression of meprins is associated with inflammatory bowel disease (IBD).
Aim i) Unravel relevant membrane proteins and reversible PTMs important for irreversible pIgR shedding
Aim ii) Determining cellular localization of the pIgR and its shedding complex during transcytosis and apical receptor release
Proteolytic release of the polymeric immunoglobulin receptor (pIgR) from intestinal epithelial cells. Ectodomain shedding of pIgR requires proteolysis at the plasma membrane. Transcytosis of pIgR and irreversible cleavage by meprin α/β enables presentation of dimeric IgA at the luminal site to fight pathogens. Meprin α/β as well as its sheddases (ADAMs and MT1-MMP) interact with TSPANs at the plasma membrane. All proteins within the shedding complex can be palmitoylated, which will be investigated as a reversible regulatory PTM for pIgR shedding.
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