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Volume 272, Number 33, Issue of August 15, 1997 pp. 20828-20834
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Protein Prenylation Is Required for the Brefeldin A-dependent Retrograde Transport from the Golgi Apparatus to the Endoplasmic Reticulum

(Received for publication, March 17, 1997, and in revised form, May 22, 1997)

N. Erwin Ivessa , Diego Gravotta ^¶ , Carmen De Lemos-Chiarandini ^¶ and Gert Kreibich ^¶

From the ^¶ Department of Cell Biology, New York University School of Medicine and Kaplan Cancer Center, New York, New York 10016 and the  Department of Molecular Genetics, University and Biocenter Vienna, A-1030 Vienna, Austria

In cells exposed to brefeldin A (BFA), enzymes of the Golgi apparatus are redistributed to the endoplasmic reticulum (ER) by retrograde membrane flow, where they may cause modifications on resident ER proteins. We have used a truncated form of the rough ER-specific type I transmembrane glycoprotein ribophorin I as a probe to detect Golgi glycosyltransferases relocated to the ER in a BFA-dependent fashion. This polypeptide (RI₃₃₂) comprises the 332 amino-terminal amino acids of ribophorin I and behaves like a luminal ER protein when expressed in HeLa cells. Upon treatment of the cells with BFA, RI₃₃₂ becomes quantitatively O-glycosylated by Golgi glycosyltransferases that are transported back to the ER. Here we demonstrate that pretreatment of the cells with lovastatin, an inhibitor of HMG-CoA reductase, abrogates this modification and that mevalonate, the product formed in the step inhibited by the drug, is able to counteract the effect of lovastatin. We also show by immunofluorescence using mannosidase II as a Golgi marker that the BFA-induced retrograde transport of Golgi enzymes is blocked by lovastatin, although electron microscopy indicates that BFA causes disassembly of the Golgi apparatus into swollen vesicles and tubules. Our observations support the role of a prenylated protein, such as the geranylgeranylated small G protein Rab6, in the retrograde transport from the Golgi apparatus to the ER, since lovastatin acts by inhibiting its prenylation.

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