NORDIHYDROGUAIARETIC ACID BLOCKS PROTEIN-TRANSPORT IN THE SECRETORY PATHWAY CAUSING REDISTRIBUTION OF GOLGI PROTEINS INTO THE ENDOPLASMIC-RETICULUM

We have investigated the effect of nordihydroguaiaretic acid (NDGA), a n inhibitor of lipoxygenase, on the intracellular protein transport an d the structure of the Golgi complex, Pulse-chase experiments and immu no-electron microscopy showed that NDGA strongly inhibits the transpor t of newly synthesized secretory proteins to the Golgi complex resulti ng in their accumulation in the endoplasmic reticulum (ER), Despite th eir retention in the ER, oligosaccharides of secretory and ED-resident proteins were processed to endoglycosidase H-resistant forms, raising the possibility that oligosaccharide-processing enzymes are redistrib uted from the Gels to the ER, Morphological observations further revea led that a-mannosidase II (a cis/medial-Golgi marker), but not TGN38 ( a trans-Gels network marker), rapidly redistributes to the ER in the p resence of NDGA, resulting in the disappearance of the characteristic Golgi structure, Upon removal of the drug, the Golgi complex was reass embled into the normal structure as judged by perinuclear staining of alpha-mannosidase II and by restoration of the secretion. These effect s of NDGA are quite similar to those of brefeldin A. However, unlike b refeldin A, NDGA did not cause a dissociation of beta-coatomer protein , a subunit of coatomer, from the Golgi membrane, On the contrary, NDG A exerted the stabilizing effect on beta-coatomer protein/membrane int eraction against the dissociation caused by brefeldin A and ATP deplet ion, Taken together, these results indicate that NDGA is a potent agen t disrupting the structure and function of the Golgi complex with a me chanism different from those known for other drugs reported so far.