Overexpression of TGF-ß 1 gene induces cell surface localized glucose-regulated protein 78-associated latency-associated peptide/TGF-ß.
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.
Oida
Takatoku
T
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Weiner
Howard L
HL
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D045683:Furin / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006031:Glycosylation; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D021382:Protein Sorting Signals; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010455:Peptides; D011498:Protein Precursors; D021382:Protein Sorting Signals; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C472416:latency-associated propeptide, TGF-beta; D045683:Furin