A NOVEL SIGNAL-TRANSDUCTION PATHWAY FROM THE ENDOPLASMIC-RETICULUM TOTHE NUCLEUS IS MEDIATED BY TRANSCRIPTION FACTOR NF-KAPPA-B

The inducible, higher eukaryotic transcription factor NF-kappa B is ac tivated by a variety of external stimuli including inflammatory cytoki nes, viral and bacterial infection and UV irradiation, Here we show th at internal stress, caused by the accumulation of proteins in the endo plasmic reticulum (ER), also induces NF-kappa B DNA binding as well as kappa B-dependent gene expression, This was observed upon expression of immunoglobulin mu chains in the absence of light chains and by trea tment of cells with several agents known to cause ER stress, such as t unicamycin, brefeldin A, 2-deoxyglucose and thapsigsargin, The transcr iption factor AP-1 was weakly induced under similar conditions, Overex pression of NF-kappa B subunits did not influence expression of the ge ne encoding grp78/BiP, a protein induced by various forms of ER stress , Likewise, the glucosidase inhibitor castanospermine, which induced g rp78/BiP expression, failed to activate NF-kappa B, while the antioxid ant dithiothreitol augmented grp78/BiP expression but prevented activa tion of NF-kappa B, Hence, NF-kappa B participates in a novel ER-nucle ar signal transduction pathway distinct from the unfolded-protein-resp onse described previously, We provide evidence that the ER can produce at least two distinct signals in response to a functional impairment. One is emitted by the presence of unfolded proteins, the other in res ponse to overloading of the organelle, for example through the overexp ression of secretory proteins.