Overexpression of TGF-β1 Gene Induces Cell Surface Localized Glucose-Regulated Protein 78-Associated Latency-Associated Peptide/TGF-β

TGF-beta plays a crucial role in immune regulation. It has been reported that pro-TGF-beta, latency-associated peptide (LAP), latent TGF-beta and/or active TGF-beta (LAP/TGF-beta) is localized on the cell surface of Foxp3(+) regulatory T cells. However, the molecular mechanism(s) of how LAP/TGF-beta is anchored on the cell membrane is unknown. In this study, we show that forced expression of human TGF-beta(1) gene by retrovirus transduction into P3U1 mouse myeloma cells, and other cell types including murine CD4(+)CD25(-) T cells, makes these cells surface LAP/TGF-beta-positive. The surface LAP/TGF-beta contains high-glycosylated, furin-processed latent TGF-beta, which is different from the low-glycosylated, furin-unprocessed intracellular form or the high-glycosylated, furin-unprocessed secreted form. Furthermore, surface LAP/TGF-beta forms a complex with the molecular chaperone glucose-regulated protein 78 (GRP78, also known as BiP), and knockdown of GRP78 reduced the expression levels of surface LAP/TGF-beta. GRP78, however, is not involved in GARP-mediated surface LAP/TGF-beta. Our results suggest that GRP78 provides an additional surface localization mechanism for LAP/TGF-beta, which may play an important role in controlling TGF-beta activity. The Journal of Immunology, 2010, 185: 3529-3535.