Nordihydroguaiaretic Acid Blocks Protein Transport in the Secretory Pathway Causing Redistribution of Golgi Proteins into the Endoplasmic Reticulum

• Published in: The Journal of biological chemistry Vol. 273; no. 5; pp. 3068 - 3075
• Main Authors: Fujiwara, T, Takami, N, Misumi, Y, Ikehara, Y
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 30-01-1998
• Subjects: Adenosine Triphosphate - metabolism; Albumins - metabolism; Animals; Biological Transport; Cells, Cultured; Coatomer Protein; Complement C3 - metabolism; COS Cells; Endoplasmic Reticulum - metabolism; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Humans; Masoprocol - pharmacology; Membrane Proteins - metabolism; Oligosaccharides - metabolism; Prealbumin - metabolism; Protease Inhibitors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.5.3068

We have investigated the effect of nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, on the intracellular protein
transport and the structure of the Golgi complex. Pulse-chase experiments and immunoelectron microscopy showed that NDGA strongly
inhibits the transport of newly synthesized secretory proteins to the Golgi complex resulting in their accumulation in the
endoplasmic reticulum (ER). Despite their retention in the ER, oligosaccharides of secretory and ER-resident proteins were
processed to endoglycosidase H-resistant forms, raising the possibility that oligosaccharide-processing enzymes are redistributed
from the Golgi to the ER. Morphological observations further revealed that α-mannosidase II (a cis / medial -Golgi marker), but not TGN38 (a trans -Golgi network marker), rapidly redistributes to the ER in the presence of NDGA, resulting in the disappearance of the characteristic
Golgi structure. Upon removal of the drug, the Golgi complex was reassembled into the normal structure as judged by perinuclear
staining of α-mannosidase II and by restoration of the secretion. These effects of NDGA are quite similar to those of brefeldin
A. However, unlike brefeldin A, NDGA did not cause a dissociation of β-coatomer protein, a subunit of coatomer, from the Golgi
membrane. On the contrary, NDGA exerted the stabilizing effect on β-coatomer protein/membrane interaction against the dissociation
caused by brefeldin A and ATP depletion. Taken together, these results indicate that NDGA is a potent agent disrupting the
structure and function of the Golgi complex with a mechanism different from those known for other drugs reported so far.